ABSTRACT
Introduction
Salivary gland malignancies are heterogeneous tumors with highly variable outcomes. Elective neck management options include observation, neck dissection (ND), and neck irradiation (NI). We sought to compare outcomes of cN0 salivary gland cancer by elective neck management.
Methods
An IRB‐approved registry was queried for cN0 salivary gland cancers and categorized based on neck management into observation, ND, NI, and ND + NI groups. cN0 included no evidence of clinical or radiographic metastatic lymphadenopathy.
Results
A total of 445 patients were included with 203 in observation, 83 ND, 71 NI, and 88 ND + NI. Median follow‐up was 60.8 months (range 0.4–258). There were 47% clinical T1 tumors, 29% T2, and 12% of each T3 and T4. Exactly 90% were cN0 and 10% with borderline lymph node(s). The major salivary gland was the most common site (74%) and the most common histologies included 28% mucoepidermoid and 20% adenoid cystic. Risk factors associated with regional recurrence include age, borderline lymph node features, pathologic T and N stage, poorly differentiated, positive margin, lymphovascular space invasion, and extranodal extension (all p < 0.05). There was no significant difference in local (9.9%–16.7%, p = 0.6) or regional (3.9%–9.4%, p = 0.76) recurrence between all four groups. Five‐year distant recurrence was significantly different at 7% for observation, 16% in ND, 25% in NI, and 37% in ND + NI (p < 0.001). Ten‐year OS estimates were 78% for observation, 66% for ND, 69% for NI, and 52% in ND + NI (p < 0.001).
Conclusion
For patients with cN0 salivary gland cancer, ND and NI yield similar regional control in appropriately selected patients. In high‐risk patients with several adverse risk features ND + NI results in favorable regional control but distant metastasis is a driving factor affecting overall survival.
Keywords: elective neck, node negative, radiation therapy, salivary gland cancer
1. Introduction
Salivary gland malignancies are rare and heterogeneous tumors, comprising < 5% of head and neck cancers. The biological heterogeneity prevents large, comparative studies and the first treatment consensus guideline was created by the American Society of Clinical Oncology (ASCO) in 2021 [1]. Definitive surgery with risk‐adapted adjuvant therapy is superior to nonsurgical management and is the standard of care [1]. Neck dissection and adjuvant radiation therapy (RT) are beneficial for nodal metastases and locally advanced disease [1, 2]. Optimal management of the clinically node‐negative (cN0) neck is undefined [3]. Elective management options for the cN0 neck include observation, neck dissection (ND), and neck irradiation (NI) for patients planning to receive adjuvant RT [3]. As surgical management is known to be superior for gross disease, the conventional paradigm for cN0 neck is often ND for tumors with high‐risk features including high grade, aggressive histology, and advanced tumor stage. NI is often performed, even in the setting of a pathologically negative ND, for patients with primary tumor risk factors warranting adjuvant RT. Tumor sites may differentially impact nodal involvement with tumors of the oral cavity rarely resulting in cervical lymph node metastases [4, 5]. The role of concurrent chemotherapy with adjuvant RT in the management of high‐risk salivary gland cancer will be determined based on the results of the recently closed study RTOG 1008.
Most studies on elective neck treatment of salivary gland cancer are small single‐institution retrospective reviews that have compared observation, ND, NI, and ND + NI for cN0 cases. The objective of this study is to compare oncologic outcomes, stratified based on neck management in a large cohort of patients.
2. Materials/Methods
An Institutional Review Board approved registry of head and neck cancers treated at a tertiary care center was queried for diagnoses of salivary gland cancer of major or minor salivary glands between 2000 and 2019. Diagnosis for inclusion in the study was based on final surgical pathology. Clinically node‐negative cases were defined as those that did not demonstrate evidence of lymphadenopathy based on physical examination and preoperative radiographic evaluation if completed. Negative, but borderline radiographic nodal features were considered ≥ 1 ipsilateral lymph node(s) measuring 0.7–1.0 cm in the short axis or bilateral, symmetric lymph nodes measuring 1.0–1.3 cm in the short axis. Lymph nodes with maximum standardized uptake values (SUV) between 2.5 and 5.0 on positron emission tomography were defined as borderline, and those with maximum SUV > 5.0 were considered clinically positive and excluded. ND was defined as surgical resection of ≥ 5 lymph nodes, not including intra‐parotid nodes standardly resected at the time of parotidectomy. Patients with 0–4 lymph nodes removed at the time of surgery were not included in the ND group. ND is routinely completed for intermediate and grade high neoplasms if that is established at the time of biopsy. ND includes ipsilateral level II–IV, with the inclusion of level I for oral cavity and submandibular gland primary tumors. Patients were evaluated for receipt of adjuvant RT, and those who received RT were classified as treated to the tumor bed with or without NI. Patients treated to tumor beds only were not included in the NI group. NI was defined as intentional coverage of at least one regional lymphatic level outside the level of the tumor bed. Patients presenting with non‐salivary specific histology of salivary gland (i.e., parotid with squamous cell carcinoma), regional or distant metastases, prior treatment for salivary gland cancer, prior head and neck radiotherapy, receiving treatment for other cancers, did not complete planned treatment, and those with > 1% missing data were excluded from the analysis.
Patients were categorized based on ipsilateral neck management: observation, ND, NI, or ND + NI. Patient demographics, disease and treatment details, and outcomes were recorded. A head and neck pathologist reevaluated any tumors with ambiguous staging or grade. Tumor margins were considered close if ≤ 5 mm from the specimen edge. Adjuvant RT is delivered in the setting of intermediate or high pathologic risk factors are present. This most commonly included pT3‐4, perineural invasion (PNI), lymphovascular space invasion (LVSI), positive LN, and close margins. If patients met the criteria for neck management and were found to have indications for adjuvant RT and had not undergone an ND, for example, if preoperative pathology was indeterminate, a second operation for ND was not recommended and NI was completed.
Patient, tumor, and treatment characteristics were compared among treatment groups with the Chi‐square test (categorical variables) or Kruskal–Wallis test (continuous variables). Local, regional, and distant recurrence were estimated with cumulative incidence and compared among treatment groups with Gray's test. Overall survival (OS) was estimated with Kaplan–Meier methods and compared with a log‐rank test. All outcomes were assessed from the date of surgery. Risk factors for local and regional recurrences were assessed with Fine and Gray regression. Multivariable analysis was not done due to a small number of events. Data were analyzed with SAS software (SAS Institute Inc., Cary, NC). All statistical tests were two‐sided, and p < 0.05 was considered statistically significant.
3. Results
A total of 445 patients met the eligibility criteria and were included in this analysis. Median follow‐up was 60.8 months (range 0.4–258.3). Patient and disease characteristics are summarized in Table 1. The major salivary gland was the most common site in 73.7% of patients (N = 328), including the parotid gland (6.1%, N = 270), submandibular gland (11.9%, N = 53), and sublingual gland (1.1%, N = 5). Minor salivary gland was the primary tumor site in 26.3% (N = 117), including oral cavity (19.3%, N = 86), nasal cavity (3.1%, N = 14), paranasal sinus (2.2%, N = 10), oropharynx (0.9%, N = 4), and larynx (0.7%, N = 3). The median age of the entire cohort was 59 years old (range 13–93). Preoperative radiographic imaging was completed in 87% of patients, with a total of 349 CT scans, 115 MRIs, and 96 PET scans completed preoperatively among all patients.
TABLE 1.
Patient and disease characteristics.
| Variable | Observation (N = 203) | ND (N = 83) | NI (N = 71) | ND + NI (N = 88) | p |
|---|---|---|---|---|---|
| N (%) | N (%) | N (%) | N (%) | ||
| Median age (range), years | 57 (14–91) | 60 (13–93) | 56 (18–88) | 63 (26–86) | 0.01 |
| Gender | |||||
| Male | 74 (36.5) | 42 (50.6) | 35 (49.3) | 42 (47.7) | 0.06 |
| Female | 129 (63.5) | 41 (49.4) | 36 (50.7) | 46 (52.3) | |
| Race | |||||
| White | 158 (79.0) | 74 (91.4) | 58 (85.3) | 79 (89.8) | 0.06 |
| Black | 32 (16.0) | 6 (7.4) | 7 (10.3) | 9 (10.2) | |
| Others | 10 (5.0) | 1 (1.2) | 3 (4.4) | 0 (0.0) | |
| Unknown | 3 | 2 | 3 | 0 | |
| Clinical T stage | < 0.001 | ||||
| T0/Tis | 0 (0) | 0 (0) | 2 (2.8) | 0 (0) | |
| T1 | 124 (61.1) | 37 (44.6) | 26 (36.6) | 19 (21.6) | |
| T2 | 47 (23.2) | 28 (33.7) | 20 (28.2) | 32 (36.4) | |
| T3 | 14 (6.9) | 11 (13.3) | 12 (16.9) | 18 (20.5) | |
| T4 | 18 (8.9) | 7 (8.4) | 11 (15.5) | 19 (21.6) | |
| Clinical N‐stage | < 0.001 | ||||
| N0 | 193 (95.1) | 75 (90.4) | 66 (93) | 68 (77.3) | |
| N0/borderline features | 10 (4.9) | 8 (9.6) | 5 (7) | 20 (22.7) | |
| Differentiation | < 0.001 | ||||
| Well | 146 (72.3) | 45 (54.2) | 27 (39.1) | 18 (20.7) | |
| Moderate | 34 (16.8) | 10 (12.0) | 17 (24.6) | 16 (18.4) | |
| Poor | 22 (10.9) | 28 (33.7) | 25 (36.2) | 53 (60.9) | |
| Unknown | 1 | 0 | 2 | 1 | |
| Tumor site | < 0.001 | ||||
| Major | 119 (58.6) | 74 (89.2) | 54 (76.1) | 81 (92.0) | |
| Minor | 84 (41.4) | 9 (10.8) | 17 (23.9) | 7 (8.0) | |
| Histology | < 0.001 | ||||
| Mucoepidermoid | 69 (34.0) | 19 (22.9) | 20 (28.2) | 16 (18.2) | |
| Adenoid cystic | 35 (17.2) | 11 (13.3) | 19 (26.8) | 24 (27.3) | |
| Acinic cell | 17 (8.4) | 16 (19.3) | 5 (7.0) | 4 (4.5) | |
| Polymorphous ADCA | 27 (13.3) | 7 (8.4) | 4 (5.6) | 4 (4.5) | |
| Adenocarcinoma | 12 (5.9) | 6 (7.2) | 6 (8.5) | 9 (10.2) | |
| Salivary duct | 5 (2.5) | 9 (10.8) | 1 (1.4) | 18 (20.5) | |
| Myoepithelial | 10 (4.9) | 2 (2.4) | 3 (4.2) | 2 (2.3) | |
| Basal cell ADCA | 7 (3.4) | 6 (7.2) | 3 (4.2) | 0 (0) | |
| Others | 21 (10.3) | 7 (8.4) | 10 (14.1) | 11 (12.5) | |
| Pathologic T‐stage | < 0.001 | ||||
| pT0/Tis | 5 (2.5) | 7 (8.4) | 0 (0.0) | 1 (1.1) | |
| pT1 | 113 (55.7) | 29 (34.9) | 16 (22.5) | 7 (8.0) | |
| pT2 | 41 (20.2) | 19 (22.9) | 15 (21.1) | 14 (15.9) | |
| pT3 | 21 (10.3) | 8 (9.6) | 17 (23.9) | 27 (30.7) | |
| pT4a | 11 (5.4) | 15 (18.1) | 14 (19.7) | 29 (33.0) | |
| pT4b | 12 (5.9) | 5 (6.0) | 5 (7.0) | 9 (10.2) | |
| pT+/NOS | 0 (0.0) | 0 (0.0) | 4 (5.6) | 1 (1.1) | |
| Pathologic N‐stage | < 0.001 | ||||
| pN0 | 68 (97.1) | 71 (85.5) | 29 (87.9) | 42 (48.3) | |
| pN+ | 2 (2.9) | 12 (14.5) | 4 (12.1) | 45 (51.7) | |
| Margins | < 0.001 | ||||
| Positive | 55 (28.2) | 15 (19.2) | 37 (54.4) | 35 (41.2) | |
| Close | 68 (34.9) | 24 (30.8) | 18 (26.5) | 26 (30.6) | |
| Negative | 72 (36.9) | 39 (50.0) | 13 (19.1) | 24 (28.2) | |
| Unknown | 8 | 5 | 3 | 3 | |
| Perineural invasion | < 0.001 | ||||
| Present | 45 (23.3) | 29 (36.7) | 29 (46.8) | 64 (78.0) | |
| Absent | 148 (76.7) | 50 (63.3) | 33 (53.2) | 18 (22.0) | |
| Unknown | 10 | 4 | 9 | 6 | |
| LVSI | < 0.001 | ||||
| Present | 18 (9.4) | 17 (21.8) | 14 (24.6) | 41 (50.6) | |
| Absent | 173 (90.6) | 61 (78.2) | 43 (75.4) | 40 (49.4) | |
| Unknown | 12 | 5 | 14 | 7 | |
| Bone invasion | 0.71 | ||||
| Present | 23 (12.0) | 8 (9.8) | 4 (7.1) | 7 (9.1) | |
| Absent | 168 (88.0) | 74 (90.2) | 52 (92.9) | 70 (90.9) | |
| Extranodal extension | < 0.001 | ||||
| Present | 1 (1.4) | 6 (7.2) | 2 (6.1) | 22 (25.3) | |
| Absent | 69 (98.6) | 77 (92.8) | 31 (93.9) | 65 (74.7) |
All patients underwent surgical resection of the primary tumor, of which 38.4% (N = 171) included ND. The median number of LN removed during ND was 23 (range 6–106). Adjuvant RT was delivered to 48.3% (N = 215) with 6.7% (N = 30) receiving concurrent chemotherapy. Adjuvant RT to the tumor bed only was delivered in 20.2% (N = 41) of patients in the observation group and 18.8% (N = 15) of patients classified in the ND alone group. NI was included in 35.7% (N = 159), and was most commonly unilateral (86.2%, N = 137). In all groups, the RT technique was most commonly intensity‐modulated RT 88.1% (N = 192), 3D conformal RT 8.7% (N = 19), 2D RT/electrons 1% (N = 2), or not specified 2.2% (N = 5). The median RT dose was 60 Gy in 30 fractions with a range from 50 Gy in 20 fractions to 74.5 Gy in 32 fractions. Of those, 78.9% (N = 172) received between 56 and 66 Gy in 28–33 fractions.
There was a statistically significant difference in age among the groups with the ND + NI group more commonly being older (p = 0.01). The ND + NI group had a higher proportion of T3 and T4 tumors as compared with the other groups: 42.1% versus 15.7% in observation, 21.7% in ND, and 32.4% in NI. ND + NI patients had the highest proportion of borderline features at 23%, compared with 5%–10% in other groups. The ND + NI group also had a higher proportion of tumors in major salivary glands, poorly differentiated tumors, pT3 and pT4 tumors, PNI, and LVSI (p < 0.001). The ND + NI group was 51.7% pathologically node‐positive compared with 2.9% in observation, 14.5% in ND, and 12.1% in the NI group (p < 0.001). The NI group had the highest ratio of positive margins (p < 0.001).
The local, regional, and distant recurrence and deaths are shown in Table 2. There was no significant difference in the incidence of local recurrence among the four groups, ranging from 9.9% to 16.7% (p = 0.6) (Figure 1A). Similarly, the 10‐year regional failure incidence rate ranged from 3.9% to 9.4% and was not statistically different (p = 0.76) (Figure 1B). The ND + NI group had the highest incidence of distant recurrence and the lowest survival.
TABLE 2.
Disease recurrences and status at follow‐up.
| None | ND | NI | ND + NI | p* | |
|---|---|---|---|---|---|
| Recurrences | |||||
| Local | 27 (13.3) | 9 (10.8) | 6 (8.5) | 8 (9.1) | 0.6 |
| Regional | 8 (3.9) | 5 (6) | 4 (5.6) | 4 (4.5) | 0.76 |
| Distant | 13 (6.4) | 12 (14.5) | 18 (25.4) | 27 (30.7) | < 0.001 |
| Status at follow‐up | < 0.001 | ||||
| Alive | 172 (84.7) | 64 (77.1) | 58 (81.7) | 57 (64.8) | |
| Dead | 31 (15.3) | 19 (22.9) | 13 (18.3) | 31 (35.2) |
Note: The * denotes p values for recurrence were calculated using the Gray test, survival status via the log‐rank test.
FIGURE 1.
Cumulative incidence of (A) Local and (B) Regional recurrences by treatment. None (observation) (n = 203), ND (n = 83), NI (n = 71), and ND + NI (n = 88) groups. [Color figure can be viewed at wileyonlinelibrary.com]
Univariate analysis revealed a significant association between local recurrence and clinical and pathologic T‐stage, pathologic N‐stage, positive margin, and PNI (Table 3). Regional recurrence was associated with age, clinical and pathologic N‐stage, borderline nodal features, poor differentiation, pathologic T‐stage, positive margin, PNI, LVSI, and extranodal extension (ENE) (all p < 0.05).
TABLE 3.
Univariate risk factors for local and regional recurrence.
| Variable | Local (50 events) | Regional (21 events) | ||||
|---|---|---|---|---|---|---|
| HR | 95% CI | p | HR | 95% CI | p | |
| Age, years | 1.07 | 0.92–1.24 | 0.37 | 1.28 | 1.01–1.61 | 0.041 |
| Gender | ||||||
| Male/female | 1.3 | 0.75–2.26 | 0.34 | 1.6 | 0.69–3.74 | 0.28 |
| Race | ||||||
| White/all others | 1.41 | 0.61–3.26 | 0.42 | 4.01 | 0.56–28.6 | 0.17 |
| Clinical T stage | ||||||
| Per 1 level increase | 1.3 | 1.06–1.6 | 0.01 | 1.11 | 0.83–1.48 | 0.48 |
| Clinical N stage | ||||||
| Borderline/N0 | 1.1 | 0.43–2.83 | 0.84 | 3.35 | 1.21–9.28 | 0.02 |
| Differentiation | ||||||
| Moderate/well | 1.59 | 0.78–3.22 | 0.2 | 1.51 | 0.39–5.88 | 0.55 |
| Poor/well | 1.86 | 0.99–3.5 | 0.06 | 4.42 | 1.7–11.5 | 0.002 |
| Salivary gland site | ||||||
| Major/minor | 0.71 | 0.4–1.25 | 0.23 | 1.58 | 0.55–4.52 | 0.39 |
| Pathologic T stage | ||||||
| Per 1 level increase | 1.4 | 1.14–1.73 | 0.001 | 1.31 | 1.01–1.69 | 0.04 |
| Pathologic N stage | ||||||
| Per 1 level increase | 1.71 | 1.24–2.35 | 0.001 | 1.96 | 1.37–2.82 | < 0.001 |
| Margins | ||||||
| Close/negative | 0.86 | 0.35–2.1 | 0.74 | 1.45 | 0.35–5.98 | 0.61 |
| Positive/negative | 2.12 | 1.05–4.25 | 0.035 | 3.41 | 1.05–11 | 0.04 |
| Perineural invasion | ||||||
| Present/absent | 2.49 | 1.34–4.61 | 0.004 | 3.09 | 1.14–8.37 | 0.026 |
| LVSI | ||||||
| Present/absent | 1.74 | 0.9–3.37 | 0.1 | 3.36 | 1.29–8.75 | 0.013 |
| Bone invasion | ||||||
| Present/absent | 3.44 | 1.74–6.78 | < 0.001 | 0.44 | 0.06–3.27 | 0.42 |
| ECE | ||||||
| Present/absent | 2.58 | 0.93–7.18 | 0.07 | 4.15 | 1.41–12.3 | 0.01 |
Distant recurrence was significantly different between the four groups (Figure 2A). The ND + NI group had a 5‐year distant recurrence rate of 37.3% compared with 6.7% in observation, 15.6% in ND, and 25.2% in NI (p < 0.001). Figure 2B demonstrates OS estimates. Survival was lowest in ND + NI group, with an estimated 10‐year survival of 52% compared with 78% in observation, 66% in ND, and 69% in NI group (p < 0.001).
FIGURE 2.
(A) Cumulative incidence of distant recurrence and (B) Kaplan–Meier estimates of overall survival by treatment for observation (n = 203), ND (n = 83), NI (n = 71), and ND + NI (n = 88) groups. [Color figure can be viewed at wileyonlinelibrary.com]
4. Discussion
Selecting patients who will benefit from elective neck management, and which type of treatment, versus observation in cN0 salivary gland cancer is challenging. Prospective studies on salivary gland cancer have solely assessed the effectiveness of systemic therapies, and there are very few studies on a large group of patients not restricted to select histological types. Guidelines for optimal management of the neck in cN0 cases, especially those of high‐grade tumors is needed, as there is a 20%–50% chance of occult metastasis [6]. A threshold of occult nodal disease > 15% is recommended for elective neck management [7]. This study presents detailed information on a large number of cN0 salivary gland cancers. There was no statistically significant difference in local or regional failure incidence among the four groups, suggesting that management based on clinical and pathologic features was appropriate. In cN0 neck, ND or NI provides durable regional control, comparable with dual‐modality therapy utilized in higher‐risk patients. Patients with borderline nodal features most commonly received ND (65%) and of those, 71% were in the ND + NI group. ND + NI patients had the highest incidence of distant metastasis, which likely resulted in inferior survival. This is associated with the higher‐risk features found in the ND + NI cohort including but not limited to poorly differentiated tumors, advanced T stage, and positive nodes (Table 1). In addition to assessing the best approach to elective neck management, this study also identifies several variables that indicate a higher risk for local and regional failure.
Nodal status is a well‐known prognostic factor for salivary gland cancer. Prognostic factors for the risk of occult nodal disease are tumor grade, histology, and location of the tumor [4, 5, 8]. In one series of 22 653 patients, salivary ductal carcinoma had a 23.6% incidence of occult lymph node metastasis as compared with 4.4% in acinar cell carcinoma [8]. Two indices have been developed to aid in determining the risk of lymph node metastases. The prognostic index by Tergaard et al. is based on histology and primary tumor location whereas the index by Wang et al. includes PNI, histology, LVSI, and ENE [4, 9]. All variables included in these indices were significant in univariate analysis in our study.
Tergaard et al. assessed the outcomes of 565 patients and found that nodal status impacted regional failure and overall survival [10]. Similarly, our study showed a significantly higher risk of local and regional failure with borderline clinical nodal status and pathologically positive lymph nodes. Although Tergaard et al. reported that ENE did not impact regional control, our data shows a significant effect of ENE and margin status on regional recurrence; with additional studies supporting either [10, 11, 12, 13]. In addition, we found tumor grade, positive margin, PNI, and LVSI also impacted regional recurrence. A number of studies have attributed a specific neck treatment modality to improved outcomes; however, most have only compared a single modality of neck management against observation. Others that have compared NI and ND versus observation are very few and reported outcomes may be skewed by lack of randomization of patients to each treatment group [6, 7, 14]. For example, most patients treated with NI as compared with ND have more high‐risk features including borderline nodal features, as highlighted in our study.
There has been much interest in determining the optimal neck management including ND, NI, or both [3, 4, 11, 14]. The recently published guideline for the management of salivary gland cancer by ASCO reported recommendations for neck management [1]. For clinically positive lymph nodes, the recommended management is ND followed by adjuvant RT. ND is moderately recommended in cN0 cases within T3/T4 tumors and high‐grade malignancies [1, 8, 15]. An NCDB assessment of high‐grade parotid cN0 malignancies reported no difference in overall survival between ND and observation [16]. A statistically significant improved 3‐year overall survival with ND was noted in T1–T2 tumors when compared with observation [16]. Some studies that reported no improvement in survival argue that ND is not necessary for cN0 [13]. However, with advances in RT, more studies showed good regional disease control with NI and less morbidity as compared with ND [6].
The ASCO guideline moderately recommends NI for all T3–T4 tumors and high‐grade malignancies, especially with the risk of microscopic nodal disease > 10% [1, 4]. Comparison of surgery alone and surgery and adjuvant RT in 87 salivary gland cancer patients resulted in improved local control and OS with the addition of adjuvant RT, unlike our study [17]. Others have reported improved regional control with NI [10, 12]. Even with most patients treated with NI presenting with more high‐risk features as compared with those given ND, our study and reports from others indicate good regional control with NI [4, 6, 7, 18].
Szewczyk et al. examined the treatment outcomes of 106 patients who underwent ND, NI, or observation [14]. There were no statistically significant differences in the demographic and clinical characteristics of each treatment group. No differences in DFS, OS, and treatment failure among the three groups, despite the ND group consisting of the highest percentage of high‐grade tumors, perhaps due to the small sample size. ND provides an opportunity for better staging and provides good regional control. Our study, similarly, showed no significant difference in local and regional disease control. ND + NI group had significantly increased distant failure incidence and worse OS, suggesting that systemic control is an important factor for improved outcomes. Several prospective studies examining the benefit of systemic therapy may identify treatment to reduce the development of distant metastases.
Several factors were identified to affect both local and regional recurrences. The presence of PNI and pathologically positive lymph nodes predict local and regional failure, similar to previously published reports. Tumor differentiation was not associated with local failure whereas high‐grade salivary gland tumors typically have increased local and regional failure risks. Exactly 40% of high‐grade malignancies had occult nodal metastases [5].
Our recommendation for the management of the cN0 neck in salivary gland cancer is in line with the ASCO guideline which recommends ND for patients with cT3‐4 or high‐grade malignancies. For patients that underwent primary tumor excision without ND but were found to have advanced T stage and/or high‐grade malignancy at the time of final pathology, warranting neck management, proceeding to adjuvant RT with NI without completion ND prevents delays in adjuvant therapy and is reasonable given the findings from our study.
As a single institution experience, selection bias may weaken the conclusion of this study. Although our institution strives for consistent decision‐making, there is likely some variation in the inclusion of ND and NI due to the retrospective nature of this review. Overall median follow‐up is ~5 years, which may be relatively short for tumors with low‐grade histology. However, a number of salivary gland cancers are aggressive with most events occurring within 3–4 years [11]. In addition, our study included > 20 histology types, made possible by the large number of patients in our study, which made it challenging to conclude the prognostic role of histology on treatment outcomes and histologic‐specific recommendations.
5. Conclusion
For patients with cN0 salivary gland cancer, ND and NI yield similar regional control in appropriately selected patients. In high‐risk patients with several adverse risk features, ND + NI results in favorable regional control but distant metastasis is a driving factor affecting overall survival.
Funding: This work was supported by the Melvin Markey Scholars Program.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
References
- 1. Geiger J. L., Ismaila N., Beadle B., et al., “Management of Salivary Gland Malignancy: ASCO Guideline,” Journal of Clinical Oncology 39, no. 17 (2021): 1909–1941. [DOI] [PubMed] [Google Scholar]
- 2. Armstrong J. G., Harrison L. B., Spiro R. H., Fass D. E., Strong E. W., and Fuks Z. Y., “Malignant Tumors of Major Salivary Gland Origin. A Matched‐Pair Analysis of the Role of Combined Surgery and Postoperative Radiotherapy,” Archives of Otolaryngology – Head & Neck Surgery 116, no. 3 (1990): 290–293. [DOI] [PubMed] [Google Scholar]
- 3. Wang X., Luo Y., Li M., Yan H., Sun M., and Fan T., “Management of Salivary Gland Carcinomas – A Review,” Oncotarget 8, no. 3 (2017): 3946–3956. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Terhaard C. H., Lubsen H., Rasch C. R., et al., “The Role of Radiotherapy in the Treatment of Malignant Salivary Gland Tumors,” International Journal of Radiation Oncology, Biology, Physics 61, no. 1 (2005): 103–111. [DOI] [PubMed] [Google Scholar]
- 5. Lloyd S., Yu J. B., Ross D. A., Wilson L. D., and Decker R. H., “A Prognostic Index for Predicting Lymph Node Metastasis in Minor Salivary Gland Cancer,” International Journal of Radiation Oncology, Biology, Physics 76, no. 1 (2010): 169–175. [DOI] [PubMed] [Google Scholar]
- 6. Herman M. P., Werning J. W., Morris C. G., Kirwan J. M., Amdur R. J., and Mendenhall W. M., “Elective Neck Management for High‐Grade Salivary Gland Carcinoma,” American Journal of Otolaryngology 34, no. 3 (2013): 205–208. [DOI] [PubMed] [Google Scholar]
- 7. Al‐Mamgani A., van Rooij P., Verduijn G. M., Meeuwis C. A., and Levendag P. C., “Long‐Term Outcomes and Quality of Life of 186 Patients With Primary Parotid Carcinoma Treated With Surgery and Radiotherapy at the Daniel den Hoed Cancer Center,” International Journal of Radiation Oncology, Biology, Physics 84, no. 1 (2012): 189–195. [DOI] [PubMed] [Google Scholar]
- 8. Xiao C. C., Zhan K. Y., White‐Gilbertson S. J., and Day T. A., “Predictors of Nodal Metastasis in Parotid Malignancies: A National Cancer Data Base Study of 22,653 Patients,” Otolaryngology and Head and Neck Surgery 154, no. 1 (2016): 121–130. [DOI] [PubMed] [Google Scholar]
- 9. Wang Y. L., Li D. S., Gan H. L., et al., “Predictive Index for Lymph Node Management of Major Salivary Gland Cancer,” Laryngoscope 122, no. 7 (2012): 1497–1506. [DOI] [PubMed] [Google Scholar]
- 10. Terhaard C. H., Lubsen H., Van der Tweel I., et al., “Salivary Gland Carcinoma: Independent Prognostic Factors for Locoregional Control, Distant Metastases, and Overall Survival: Results of the Dutch Head and Neck Oncology Cooperative Group,” Head & Neck 26, no. 8 (2004): 681–693. [DOI] [PubMed] [Google Scholar]
- 11. Feinstein T. M., Lai S. Y., Lenzner D., et al., “Prognostic Factors in Patients With High‐Risk Locally Advanced Salivary Gland Cancers Treated With Surgery and Postoperative Radiotherapy,” Head & Neck 33, no. 3 (2011): 318–323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Cho J. K., Lim B. W., Kim E. H., et al., “Low‐Grade Salivary Gland Cancers: Treatment Outcomes, Extent of Surgery and Indications for Postoperative Adjuvant Radiation Therapy,” Annals of Surgical Oncology 23, no. 13 (2016): 4368–4375. [DOI] [PubMed] [Google Scholar]
- 13. Israel Y., Rachmiel A., Gourevich K., and Nagler R., “Kaplan‐Meier Analysis of Salivary Gland Tumors: Prognosis and Long‐Term Survival,” Journal of Cancer Research and Clinical Oncology 145, no. 8 (2019): 2123–2130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Szewczyk M., Golusiński P., Pazdrowski J., Pieńkowski P., and Golusiński W. J., “Management of Clinically Negative Neck in Salivary Gland Cancers – Elective Neck Dissection, Irradiation, or Surveillance?,” Contemporary Oncology 23, no. 3 (2019): 169–173. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Teymoortash A. and Werner J. A., “Value of Neck Dissection in Patients With Cancer of the Parotid Gland and a Clinical N0 Neck,” Onkologie 25, no. 2 (2002): 122–126. [DOI] [PubMed] [Google Scholar]
- 16. Harbison R. A., Gray A. J., Westling T., et al., “The Role of Elective Neck Dissection in High‐Grade Parotid Malignancy: A Hospital‐Based Cohort Study,” Laryngoscope 130, no. 6 (2020): 1487–1495. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. North C. A., Lee D. J., Piantadosi S., Zahurak M., and Johns M. E., “Carcinoma of the Major Salivary Glands Treated by Surgery or Surgery Plus Postoperative Radiotherapy,” International Journal of Radiation Oncology, Biology, Physics 18, no. 6 (1990): 1319–1326. [DOI] [PubMed] [Google Scholar]
- 18. Chen A. M., Garcia J., Lee N. Y., Bucci M. K., and Eisele D. W., “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?,” International Journal of Radiation Oncology, Biology, Physics 67, no. 4 (2007): 988–994. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.