Vincent Vander Poorten
A minority of patients with salivary gland carcinomas presents with clinically or radiologically obvious cervical lymph node metastasis. These patients’ prognosis following treatment is significantly worse than that of patients with a clinically uninvolved neck. Adequate management of this aspect of the disease is thus of vital importance. There is little controversy on the management of clinically evident metastases. Primary surgery aiming at removal of all obvious suspected nodal disease will almost invariably result in pathological confirmation of the preoperative suspicion, and then entail postoperative radiotherapy, which, for all sites, improves locoregional control and survival. The optimal treatment of the clinically and radiologically uninvolved neck does continue to provoke discussion. It is not the question of whether or not to treat the neck that is the problem, as there is wide agreement on the tumor and the patient factors that make it more likely that the lymph nodes harbor occult metastases. When these factors are present, the neck should be electively treated. The major discussion, however, revolves around the best treatment strategy to use once the decision to proceed with neck treatment is made. On the one hand, there are the clinicians who prefer to treat those patients with an elective neck dissection, followed by postoperative radiotherapy on indication. On the other hand, others favor radiotherapy over elective neck dissection in this scenario. The rationale behind these two strategies is summarized.
Keywords: salivary gland carcinoma, clinically negative neck, elective neck dissection, elective radiotherapy, clinically positive neck, therapeutic neck dissection, neck metastasis
Globally, the incidence of salivary gland carcinomas is 0.4 to 13.5 cases per 100,000 people per year; in the United States, the incidence rate is 1 per 100,000 people per year. The European incidences appear to be lower, with Belgium, the Netherlands, the United Kingdom, and Finland reporting around 0.6 to 0.7 cases per 100,000 people per year. A Danish population-based study reported a crude incidence of 1.1 per 100,000 people per year.1
Around 70% of these carcinomas arise in the largest gland, the parotid,2 and 10 to 25% of salivary carcinomas arise in the minor salivary glands.3 The rest are submandibular carcinomas, with sublingual carcinomas being very rare.
Prognostic indicators explaining the observed variability in chance of cure following treatment include patient, tumor, and treatment characteristics. Tumor characteristics with prognostic impact include anatomic site of the affected salivary gland, histotype of the tumor (22 malignant types in the most recent 2017 WHO classification),4 TNM stage,5 and specific growth characteristics (perineural/intraneural invasion, lymphatic invasion, surgical margins, extraglandular extension), which can be observed histopathologically following resection. One of the tumor-related factors with a strong independent prognostic impact is regional metastasis, as reflected in the clinical and pathological N-classification.6
Evaluation of the neck is mandatory whenever a salivary malignancy is suspected on clinical grounds. Available options, both for the primary and the neck, are ultrasound, which allows for ultrasound-guided fine-needle aspiration, CT scanning (Fig. 18.1), which is superior for bone detail, and MR imaging, which is strongly advised when tumor mobility is impaired, and which has a superior soft-tissue detail, including visualization of perineural extension (Fig. 18.2).
In clinically suspected or fine-needle aspiration cytology (FNAC) proven malignancy, before embarking on locoregional therapy, positron emission tomography (PET) with or without CT co-localization (PET-CT) is mainly important for detecting disease recurrence and to exclude (gross) distant disease. It is important to note that this modality fails in differentiating benign from malignant disease, as Warthin’s tumors and pleomorphic adenomas show an increased uptake (high false-positive rate), and not infrequently, malignant tumors are not fluoro- deoxyglucose-avid (high false-negative rate).13 7
18.2 Treatment of the Neck According to the Gland of Origin of the Primary Tumor
18.2.1 Parotid Carcinoma
The Clinically Positive Neck
Regional metastasis is clinically and/or radiologically evident at presentation (clinically positive [cN + ] disease) in 14 to 29% of patients.6 8 This percentage increases in high-grade tumors and advanced T-status tumors.910 The lymph node levels most frequently involved are levels II, III, and IV.811 Parotid cancer-related cN+disease requires a (modified) radical neck dissection, removing levels I to V.12 This therapeutic comprehensive neck dissection implies radicality toward nonlymphatic structures (nerve XI, jugular vein, or sternocleidomastoid muscle) depending on proximity of or involvement by lymph node metastases13 (Fig. 18.3a, Fig. 18.4). Recent studies confirmed this “old knowledge”; rates of pathologically positive (pN +) involvement in a recent study from Memorial Sloan Kettering Cancer Center were 52% in level I, 77% in level II, 73% in level III, 53% in level IV, and 40% in level V.14 In a comparable study from Korea, rates of pN + involvement were 43% in level I, 90% in level II, 40% in level III, 57% in level IV, and still 43% in level V.15
As such, clinical neck disease implies a well-accepted negative prognostic value,6.16 but recent reports revealed the independent negative prognostic impact of an increasing “lymph-node density,” which is the ratio of the number of metastatic nodes to the total number of lymph nodes removed.17.18
A sometimes-overlooked problem is the deep lobe intraparotid lymph nodes. A significant proportion (53-65%) of patients with pN + disease on neck dissection will also have metastatic deposits in the “first echelon” intraparotid lymph nodes.8,11 When a neck dissection is needed for removal of cN + disease, it seems logical and consequent that a deep lobe parotidectomy is performed to address this problem. There is usually no discussion on performing this type of “total parotidectomy” for large tumors, deep lobe tumors, or tumors that have already caused a seventh cranial nerve (CN VII) paralysis (Fig. 18.4), but the controversy surrounds the early-stage tumors with normal facial nerve function that need a therapeutic neck dissection19 (Fig. 18.3a). Authors from Mayo Clinic recommend performing a deep-lobe parotidectomy in high-grade tumors, especially if an intraparotid node in the specimen of the initially performed superficial parotidectomy is positive on frozen section20 (Fig. 18.3 a, b). The practical problem here is that preoperative grading (based on FNAC) is infrequently available for parotid cancer patients. The Koln group published a series of 142 patients in 2008, where, in their total parotidectomy specimens, 1 to 11 parotid lymph nodes were retrieved. Eighty percent of these parotid nodes were involved in cN0/ pN + patients.11 While there is no direct evidence that resection of these nodes increases locoregional control in salivary gland cancer, this evidence is available in skin cancer, metastatic to the parotid. In this disease, a 20% local recurrence rate—the majority of which occurred in the parotid bed—was observed in patients treated with superficial parotidectomy (the deep lobe remaining in situ), despite being treated with postoperative radiotherapy.21,22
It is well accepted that pN + patients with salivary gland cancer need postoperative radiotherapy to the parotid bed and the ipsilateral neck. In this setting, adjuvant radiation not only doubles the rate of locoregional control, but also improves surviv- al.23,24 Two recent reports documented the benefit of a postoperative, platinum-based, concomitant chemoradiation scheme for high-risk major salivary gland carcinomas, and the approach certainly merits further research.25
Fig. 18.3 (a) The same patient as in Fig. 18.2, following a retrograde cranial nerve (CN) VII dissection. Intraoperatively, the facial nerve found to be displaced anterosuperiorly, but ultimately uninvolved.
A total conservative parotidectomy was possible, including a deep lobe parotidectomy, in conjunction with a therapeutic neck dissection (ND I-V, sternocleidomastoid, CN XI).12 This picture was taken before removal of the last part of the deep lobe from underneath the main trunk of the facial nerve. (b) Another patient with total conservative parotidectomy in conjunction with a selective neck dissection of level II.
The Clinically Negative Neck
Observation, Elective Neck Dissection with or without Postoperative Radiation, or Elective Neck Irradiation
The rates of pN + disease, in patients who are defined as cN0 following clinical examination and high-quality imaging, are between 12 and 49%. This variation between series derives from the different tendency to regional metastasis of the plethora of salivary gland cancer histotypes, within which there even exist different grades, again determining metastatic behavior.8,10,11,26,27,28
For patients presenting with a cN0 parotid carcinoma, we usually try to estimate the theoretical risk of pN + disease, from the presence of established risk factors for occult neck disease. We then decide to treat the cN0 neck when the combined presence of different risk factors implies a probability that exceeds the threshold of 15 to 20%.
Among identified risk factors that predict micrometastatic disease in cN0 patients are clinical and histopathological factors. Clinical factors are age in the sixth decade or older, presence of pain, seventh nerve dysfunction, and locally advanced disease as reflected in the T-status. Histological factors include histotype and grade, extraglandular soft-tissue invasion, and lymphatic invasion.8,26,28,29,30
Histotypes that imply a high prevalence (> 50%) of occult nodal disease are salivary duct carcinoma (SDC), undifferentiated carcinoma (UC), adenocarcinoma not otherwise specified (AC- NOS), high-grade mucoepidermoid carcinoma (HG-MEC), and squamous cell carcinoma (SCC).8.10 Textbook knowledge classically teaches that parotid adenoid cystic carcinoma (AdCC) has a low tendency to regional metastasis. Recently, however, a scrutinized analysis of the available literature revealed a 14.5% lymph node metastasis rate in parotid cN0 AdCC.31 The same authors identified a high-grade subgroup in parotid AdCC (AdCC-HGT) that implies a pN + rate of up to 57%.32 Acinic cell carcinoma (AcCC) and low-grade MEC are generally considered to have a low rate of pN + disease; nevertheless, authors routinely performing elective neck dissection (END) in patients with these subtypes also report higher-than-expected rates of occult nodal disease.10,11 Furthermore, also in AcCC, nowadays there is a high-grade subtype, which implies a higher risk.33 To complicate the matter, early-stage cancers and low-grade cancers can also present with cN0pN + disease.14,28,34 Stenner et al performed END in T1N0 and T2N0 patients and found a pN + rate of 21%.14,28,34
Fig.18.4 Total radical parotidectomy including resection of involved skin and inferior half of auricle as well as masseter muscle (to the right) and a radical neck dissection (ND I-V, SCM, IJV, CNXI; to the left).12 In the same procedure a static CN VII correction as well as a free anterolateral thigh muscle/skin flap is used for reconstruction. Postoperative radiotherapy is mandatory.
Available management options for the cN0 neck include observation, END with or without postoperative radiation on indication, and elective neck irradiation (ENI).
When a decision has been made to treat the neck, the first possible option is by elective neck surgery. Some authors propose a routine END for every patient with suspected or known parotid cancer.10.27.34.35 Zbaren et al substantiate this recommendation by their reporting of a 22% occult rate in operated patients. These END patients then had an improved 5-year rate of locoregional control when compared to the observation group. These findings have to be interpreted in the context that only a minority of the patients in this series (14/83) received radiotherapy; as such, it is plausible to argue that similar oncologic outcomes could have been obtained by systematic use of ENI in all of these patients.9, 27,36 Nobis et al report a 39% occult nodal disease rate, and Sten- nert et al report even a 45% rate in a series where all patients underwent neck dissection.10.35 A Brazilian group reported a 37% rate of occult nodal disease, heralded by advanced T-status, severe desmoplasia, and histologic type (UC, HG-MEC, ACNOS, SDC, and SCC had a combined occult rate of 68%).26 The problem here is that, of these factors, T-status is frequently the only one available in the preoperative setting.
A second effective option is ENI in patients who are defined “high risk” based on definitive histopathology of the resected primary.24,29,30,36,37 This strategy is appealing to many clinicians, because many of the factors that imply a “high-risk” status only become clear following pathological examination of the resected primary (exact histotype, exact grade, extraparenchymal extension, lymphovascular invasion). As already stated, pre- and perioperative histotyping and grading of salivary carcinomas are frequently problematic (accuracy 51-62%),13.29.38 whereas this information is much more reliable in the postoperative setting. When there is an indication for postoperative radiotherapy to the primary (based on final histopathology of the resected specimen), it parallels the indications for ENI of the unoperated cN0 neck. In the series of Herman et al,36 the cN0 patients selected for ENI had a 100% regional control at a median follow-up of more than 5 years, as opposed to 10% regional recurrence in patients treated with END. Another supportive study is the one by Chen et al, who reported a 0% 10-year regional recurrence rate in patients with a salivary gland cancer and a cN0 neck having undergone ENI, as opposed to a 26% failure rate in operated patients.39 While this sounds convincing, a selection bias in these data is not unlikely. Another argument in favor of ENI is the fact that patients who undergo END still need radiotherapy when a cN0 neck turns out to be pN + .24,36,37
The question of which approach to the cN0 neck in patients with parotid carcinoma is the best one, END with—on indication—postoperative radiation therapy, or immediate ENI, can only be answered reliably by conducting a prospective randomized trial. Given the rarity of the disease, such a trial can only be organized on a multicenter level.
Until that moment, different authors have tried different strategies to fine-tune the choice between the two modalities.
Preoperative ultrasound-guided FNAC of the neck and generous use of perioperative frozen section pathology have been advocated. The author’s policy is to perform a standard, selective level II dissection in all preoperatively known carcinomas with a cN0 neck, before starting the parotidectomy. Frozen section analysis of the level II nodes is then available by the time the parotidectomy is finished, and if micrometastases are revealed, the neck is upstaged to pN + and a comprehensive neck dissection follows.1 Similarly, other authors have promoted the concept of “level I and II node sampling” in high-risk patients.40
Which Levels to Address in Elective Neck Treatment of Parotid Carcinoma Patients?
The analysis of END specimens has given us an indication of which levels to address with either surgery or radiotherapy. The pivotal MSKCC study from Armstrong et al in 1992 concludes that the neck levels to be addressed are levels II, III, and IV. These findings are corroborated by recent studies confirming that, in cN0 necks, disease is rather rarely found in levels I and V.8,14,30
Practical Approach to the cN0 Neck in Parotid Carcinoma Patients: A Proposal of Options
We recently published an overview of three possible scenarios that can be encountered in the clinical reality in dealing with the cN0 neck in salivary gland cancer19:
• Scenario 1: There is a low risk of occult nodal disease (T1-T2 tumors, low-grade tumor, young patients):
* A “wait-and-see” management can be justified.14 о Alternatively, a selective level II dissection and frozen section can be performed at the beginning of the procedure, followed by a modified radical neck dissection in the rare cases where disease is present.1 о A minority of authors would recommend a systematic END.10,11,27,34
• Scenario 2: Risk factors for occult nodal disease are discovered only after final histopathology of the primary is available (high grade and/or high stage):
* ENI is recommended.29,36
• Scenario 3: High risk of occult nodal disease preoperatively certain:
* END (II-IVor Ib-IV) and postoperative neck radiotherapy based on the histopathological findings in the primary and the neck specimen.
* ENI, especially if adjuvant radiotherapy for the primary tumor is already likely.29,36,37,41
* Superselective level II dissection with extension to a comprehensive neck dissection if disease is found in level II (Fig. 18.3b). If no pathologically positive nodes are found on frozen section, then radiotherapy to the neck is indicated based on the histopathological findings on the primary.1.13
We consider extending the dissection to levels I and V in specific anatomical situations, such as primary tumors located anteriorly in the parotid, where metastases to level I are more likely, or large tumors in the parotid tail, where there is increased risk of spread to level V. Other authors systematically dissect levels I and II40 or levels I to III.35 They also perform frozen sections and convert to comprehensive neck dissection in the presence of occult nodal disease. We consider the rationale behind systematic dissection of level I to be inconsistent, given the low incidence of disease in level I in cN0 necks, as described in the landmark study by Armstrong et al.8 Furthermore, in this study, all of the few patients with positive level I nodes also had positive level II nodes, which would also have been detected if limiting the dissection for frozen section to level II. Recent studies also confirm a low rate of cN0pN + in level I.14.30
18.2.2 Submandibular Gland Carcinoma
Reported rates of lymph node metastasis in submandibular gland cancer vary. A Japanese study reported pN + status as a function of T-status of the primary (T1: 0%; T2: 33%; T3: 57%; and T4: 100%).42 In our own series, cN + disease at diagnosis was observed in 17% of the patients, but in cN0 patients treated with END, an occult rate of a further 22% was found. Survival decreased when comparing patients without clinically palpable regional metastases (5-year survival rate, 56%) to patients who presented with regional metastases (5-year survival rate, 14%; p=0.003).43 A recent study from Korea described similar findings, with a drop in 5-year overall survival from 40% for cN0 to 9% for cN + patients.44
The Clinically Positive Neck
The standard treatment for a preoperatively known submandibular gland cancer has shifted from a universally applied (both for cN0 and cN +) aggressive and extended surgery as monotherapy,45 to a more functional procedure, tailored to the locally involved anatomy, followed by postoperative radiother- apy.43,46,47,48 The standard operation in the past included the submandibular gland in a radical neck dissection, often with en bloc excision of the floor of mouth and lower rim of the mandi- ble.45 Given the reported rates of 40% pN + in level IV and 25% in level V, there is no discussion that for obvious cN + disease, a comprehensive levels I to V neck dissection preserving the nonlymphatic structures (internal jugular vein, sternomastoid muscle, and spinal accessory nerve), whenever possible, remains the standard of care.13.48
The Clinically Negative Neck
For the preoperatively known submandibular gland cancer with otherwise cN0 neck (Fig. 18.1, Fig. 18.5, Fig. 18.6) in recent decades, there has been a shift toward conservative surgery (functional END). The MSKCC group47 documented a rise in the use of levels I to III (supraomohyoid) neck dissection from none of the surgeries from 1939 to 1965, to 38% in the study period 1966 to 1982. Similarly, in the Netherlands’ Cancer Institute, the levels I to III dissection comprising the submandibular gland accounted for 66% of operative procedures in the period 1973 to 1983, and for 71% of the procedures between 1984 and 1994.43 The point these rather old studies make, that is, including the submandibular gland in an SND levels I to III being the minimal procedure, continues to stand. The occult rates found (21% in a recent American study,49 22% in our Amsterdam study, and 23% for AdCC—the most frequent malignant neoplasm of the submandibular gland—in a recent review)31 justify performing more than a simple gland excision. The extent of the neck dissection (levels I—III) was again justified by a contemporary Japanese study that reported only levels I, II, and III being involved in cN0pN + patients (Fig. 18.5, Fig. 18.6). Recently, it has been suggested that END can be omitted for T1 cancers, but T1 cancers are rare, so we believe it is safer have to have a standardized approach, and recommend elective management of the neck in all cN0 cases. From our perspective, more data are required to change this recommendation.49
18.2.3 Sublingual Gland Cancer
These are very rare tumors that are malignant in over 80% of the cases.50 In over 80% again, they present in an advanced stage (III or IV, based on the T3/T4a classification of the primary) at di- agnosis.51 Most authors recommend holding the same rule as for submandibular cancer, that is, the minimal procedure for a cN0 neck being an SND levels I to III, including resection of the floor of mouth and the sublingual gland. This seems to be substantiated by a recent thorough literature review focusing on AdCC—again the most frequently encountered histotype in this site—reporting an occult nodal disease rate of 25%.31
Fig. 18.5 Same patientas in Fig. 18.1. Procedure performed for cT3N0 adenoid cystic carcinoma of the left submandibular gland. Dissection of level I, including skin and platysma. Snapshot of the cutting of the lingual nerve branch to the submandibular ganglion.
Fig. 18.6 Same patient as in Fig. 18.1 and Fig. 18.5. Additionally, levels II and III were dissected (ND I-III)12 and the final pathological stage was pT3pN0. Postoperative radiotherapy of the neck was indicated (intensity-modulated radiation therapy of 66 Gy) and the patient has completed 10 years of follow-up without evidence of recurrence.
18.2.4 Minor Salivary Gland Cancer
The Clinically Positive Neck
Clinical or radiological evidence of regional lymph node metastasis exists in about one in six minor salivary gland cancer (MiSGC) patients, and then obviously surgical treatment of the neck, that is, a comprehensive levels I to V neck dissection is indicated.3
The Clinically Negative Neck
END is indicated when the risk of subclinical disease in a cN0 neck exceeds 15 to 20%. When the neck is surgically entered as an approach to the primary, it is logical to also address the neck surgically. Generally, the attitude among surgeons is that the occult metastatic rate, as estimated from the appearance of regional disease in the untreated cN0 neck, is too low to justify END.3 This has been recently substantiated for laryngeal, sinonasal, external acoustic meatus, and lacrimal gland origin.52 In patients with oral cavity and oropharyngeal MiSGC,53 however, and in patients with high-grade cancers such as high-grade MEC3 or high-grade AdCC,32 the occult rates largely exceed 20% and END is indicated. One remarkable study revealed a high rate of occult disease (47%) in a series of cN0 nasopharyngeal MiSGC patients where the primary was amenable to surgery.54
In MiSGC patients in general, if neck dissection reveals metastatic disease, postoperative radiotherapy improves locoregion- al control and survival.24
 Vander Poorten V, Bradley PJ, Takes RP, Rinaldo A, WoolgarJA, Ferlito A. Diagnosis and management of parotid carcinoma with a special focus on recent advances in molecular biology. Head Neck. 2012; 34(3):429-440
 Van Eycken L. Head and neck cancer. In: Van Eycken L, ed. Cancer Incidence in Belgium 2004-2005. Saint-Josse-ten-Noode: Belgian Cancer Registry; 2008:41
 Vander Poorten V, Hunt J, Bradley PJ, et al. Recent trends in the management of minor salivary gland carcinoma. Head Neck. 2014; 36(3):444-455
 El-Naggar AK, John KC, Grandis JR, Takata T, Slootweg PJ, eds. WHO classification of tumours of salivary glands. In: WHO classification of Head and Neck Tumours.4th ed. Lyon: IARC; 2017:160-184
 UICC. Major salivary glands. In: Brierley JD, Gospodarowicz M, Wittekind C, eds. TNM Classification of Malignant Tumours. 8th ed. Oxford: Wiley-Blackwell; 2017;47-51
 Vander Poorten V, Hart A, Vauterin T, et al. Prognostic index for patients with parotid carcinoma: international external validation in a Belgian-German da- tabase.Cancer. 2009; 115(3):540-550
 Razfar A, Heron DE, Branstetter BF, IV, Seethala RR, Ferris RL. Positron emission tomography-computed tomography adds to the management of salivary gland malignancies. Laryngoscope. 2010; 120(4):734-738
 Armstrong JG, Harrison LB, Thaler HT, et al. The indications for elective treatment ofthe neck in cancerofthe majorsalivaryglands. Cancer. 1992; 69(3):615-619
 Zbàren P, Schüpbach J, Nuyens M, Stauffer E, Greiner R, Hàusler R. Carcinoma of the parotid gland. AmJ Surg. 2003; 186(1):57-62
 Stennert E, Kisner D, Jungehuelsing M, et al. High incidence of lymph node metastasis in major salivary gland cancer. Arch Otolaryngol Head Neck Surg. 2003; 129(7):720-723
 Klussmann JP, Ponert T, Mueller RP, Dienes HP, Guntinas-Lichius O. Patterns of lymph node spread and its influence on outcome in resectable parotid cancer. EurJ Surg Oncol. 2008; 34(8):932-937
 Ferlito A, Robbins KT, Shah JP, et al. Proposal for a rational classification of neck dissections. Head Neck. 2011; 33(3):445-450
 Medina J, Zbàren P, Bradley PJ. Management of regional metastases of malignant salivary gland neoplasms. Adv Otorhinolaryngol. 2016; 78:132-140
 AliS, Palmer FL, DiLorenzo M, Shah JP, Patel SG, Ganly I. Treatment of the neck in carcinoma of the parotid gland. Ann Surg Oncol. 2014; 21(9):3042-3048
 Yoo SH, Roh JL, Kim SO, et al. Patterns and treatment of neck metastases in patients with salivary gland cancers.J Surg Oncol. 2015; 111(8):1000-1006
 Ali S, Palmer FL, Yu C, et al. A predictive nomogram for recurrence of carcinoma of the major salivary glands. JAMA Otolaryngol Head Neck Surg. 2013; 139(7):698-705
 Hong HR, Roh JL, Cho KJ, Choi SH, Nam SY, Kim SY. Prognostic value of lymph node density in high-grade salivary gland cancers. J Surg Oncol. 2015; 111 (6):784-789
 Suzuki H, Hanai N, Hirakawa H, Nishikawa D, Hasegawa Y. Lymph node density is a prognostic factor in patients with major salivary gland carcinoma. Oncol Lett. 2015; 10(6):3523-3528
 Lombardi D, McGurk M, Vander Poorten V, et al. Surgical treatment of salivary malignant tumors. Oral Oncol. 2017; 65:102-113
 Olsen KD, Moore EJ. Deep lobe parotidectomy: clinical rationale in the management of primary and metastatic cancer. Eur Arch Otorhinolaryngol. 2014; 271(5):1181-1185
 O'Brien CJ, McNeil EB, McMahon JD, Pathak I, Lauer CS, Jackson MA. Significance of clinical stage, extent of surgery, and pathologic findings in metastatic cutaneous squamous carcinoma of the parotid gland. Head Neck. 2002; 24(5):417-422
 Thom JJ, Moore EJ, Price DL, Kasperbauer JL, Starkman SJ, Olsen KD. The role of total parotidectomy for metastatic cutaneous squamous cell carcinoma and malignant melanoma. JAMA Otolaryngol Head Neck Surg. 2014; 140 (6):548-554
 Armstrong JG, Harrison LB, Spiro RH, Fass DE, Strong EW, Fuks ZY. Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy. Arch Otolaryngol Head Neck Surg. 1990; 116(3):290-293
 Terhaard CH, Lubsen H, Rasch CR, et al. Dutch Head and Neck Oncology Cooperative Group. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys. 2005; 61 (1):103-111
 Vander Poorten V, Meulemans J, Delaere P, Nuyts S, Clement P. Molecular markers and chemotherapy for advanced salivary cancer. Curr Otorhinolaryngol Rep. 2014; 2(2):85-96
 Régis De Brito Santos I, Kowalski LP, Cavalcante De Araujo V, Flâvia Logullo A, Magrin J. Multivariate analysis of risk factors for neck metastases in surgically treated parotid carcinomas. Arch Otolaryngol Head Neck Surg. 2001; 127 (1) :56-60
 Zbàren P, Schüpbach J, Nuyens M, Stauffer E. Elective neck dissection versus observation in primary parotid carcinoma. Otolaryngol Head Neck Surg. 2005; 132(3):387-391
 Kawata R, Koutetsu L, Yoshimura K, Nishikawa S, Takenaka H. Indication for elective neck dissection for N0 carcinoma of the parotid gland: a single institution's 20-year experience. Acta Otolaryngol. 2010; 130 (2) :286-292
 Frankenthaler RA, Byers RM, Luna MA, Callender DL, Wolf P, Goepfert H. Predicting occult lymph node metastasis in parotid cancer. Arch Otolaryngol Head Neck Surg. 1993; 119(5):517-520
 Lau VH, Aouad R, Farwell DG, Donald PJ, Chen AM. Patterns of nodal involvement for clinically N0 salivary gland carcinoma: refining the role of elective neck irradiation. Head Neck. 2014; 36(10):1435-1439
 Silver CE, Bradley PJ, Barnes L, et al. International Head and Neck Scientific Group. Cervical lymph node metastasis in adenoid cystic carcinoma of the major salivary glands. J Laryngol Otol. 2017; 131(2):96-105
 Hellquist H, Skâlovâ A, Barnes L, et al. Cervical lymph node metastasis in high-grade transformation of head and neck adenoid cystic carcinoma: a collective international review. AdvTher. 2016; 33(3):357-368
 Vander Poorten V, Triantafyllou A, Thompson LD, et al. Salivary acinic cell carcinoma: reappraisal and update. Eur Arch Otorhinolaryngol. 2016; 273 (11):3511-3531
 Stenner M, Molls C, Luers JC, Beutner D, Klussmann JP, Huettenbrink KB. Occurrence of lymph node metastasis in early-stage parotid gland cancer. Eur Arch Otorhinolaryngol. 2012; 269(2):643-648
 Nobis CP, Rohleder NH, Wolff KD, Wagenpfeil S, Scherer EQ, Kesting MR. Head and neck salivary gland carcinomas-elective neck dissection, yes or no? J Oral Maxillofac Surg. 2014; 72(1):205-210
 Herman MP, Werning JW, Morris CG, Kirwan JM, Amdur RJ, Mendenhall WM. Elective neck management for high-grade salivary gland carcinoma. Am J Otolaryngol. 2013; 34(3):205-208
 Chen AM, Garcia J, Lee NY, Bucci MK, Eisele DW. Patterns of nodal relapse after surgery and postoperative radiation therapy for carcinomas of the major and minor salivary glands: what is the role of elective neck irradiation? Int J Radiat Oncol Biol Phys. 2007; 67(4):988-994
 Westra WH. The surgical pathology of salivary gland neoplasms. Otolaryngol Clin North Am. 1999; 32(5):919-943
 Chen AM, Granchi PJ, Garcia J, Bucci MK, Fu KK, Eisele DW. Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys. 2007; 67(4):982-987
 Korkmaz H, Yoo GH, Du W, et al. Predictors of nodal metastasis in salivary gland cancer. J Surg Oncol. 2002; 80(4):186-189
 Frankenthaler RA, Luna MA, Lee SS, et al. Prognostic variables in parotid gland cancer. Arch Otolaryngol Head Neck Surg. 1991; 117(11):1251-1256
 Beppu T, Kamata SE, Kawabata K, et al. Prophylactic neck dissection for submandibular gland cancer. Nippon Jibiinkoka Gakkai Kaiho. 2003; 106(8):831-837
 Vander Poorten VL, Balm AJ, Hilgers FJ, et al. Prognostic factors for long term results of the treatment of patients with malignant submandibular gland tumors. Cancer. 1999; 85(10):2255-2264
 Roh JL, Choi SH, Lee SW, Cho KJ, Nam SY, Kim SY. Carcinomas arising in the submandibular gland: high propensity for systemic failure. J Surg Oncol. 2008; 97(6):533-537
 Conley J, Myers E, Cole R. Analysis of 115 patients with tumors of the submandibular gland. Ann Otol Rhinol Laryngol. 1972; 81(3):323-330
 Weber RS, Byers RM, Petit B, Wolf P, Ang K, Luna M. Submandibular gland tumors. Adverse histologic factors and therapeutic implications. Arch Otolaryngol Head Neck Surg. 1990; 116(9):1055-1060
 Spiro RH, Armstrong J, Harrison L, Geller NL, Lin SY, Strong EW. Carcinoma of major salivary glands. Recent trends. Arch Otolaryngol Head Neck Surg. 1989; 115(3):316-321
 Han MW, Cho KJ, Roh JL, Choi SH, Nam SY, Kim SY. Patterns of lymph node metastasis and their influence on outcomes in patients with submandibular gland carcinoma. J Surg Oncol. 2012; 106(4):475-480
 Pohar S, Venkatesan V, Stitt LW, et al. Results in the management of malignant submandibular tumours and guidelines for elective neck treatment. J Otolaryngol Head Neck Surg. 2011; 40(3):191-195
 Sun G, Yang X, Tang E, Wen J, Lu M, Hu Q. The treatment of sublingual gland tumours. Int J Oral Maxillofac Surg. 2010; 39(9):863-868
 Zdanowski R, Dias FL, Barbosa MM, et al. Sublingual gland tumors: clinical, pathologic, and therapeutic analysis of 13 patients treated in a single institution. Head Neck. 2011; 33(4):476-481
 Bishop JA, Barnes EL, Slootweg PJ, et al. International Head and Neck Scientific Group. Cervical lymph node metastasis in adenoid cystic carcinoma of the sino- nasal tract, nasopharynx, lacrimal glands and external auditory canal: a collective international review. J Laryngol Otol. 2016; 130(12):1093-1097
 Suarez C, Barnes L, Silver CE, et al. Cervical lymph node metastasis in adenoid cystic carcinoma of oral cavity and oropharynx: a collective international review. Auris Nasus Larynx. 2016; 43(5):477-484
 Schramm VL, Jr, Imola MJ. Management of nasopharyngeal salivary gland malignancy. Laryngoscope. 2001; 111(9):1533-1544