Key Points
Question
Is margin status associated with local control and survival in patients with salivary gland cancer?
Findings
In this cohort study of 837 patients with surgically treated salivary gland cancer, patients with positive surgical margins were at increased risk for poorer local control and survival and had better outcomes with postoperative adjuvant radiotherapy. In patients with close margins who had low-risk histologic-type and low-stage I/II disease, patients who did not receive adjuvant radiotherapy had comparable local control to those who received adjuvant radiotherapy.
Meaning
The findings of this study suggest that, when planning adjuvant radiotherapy in patients with close margins, individual histologic risk must be considered; observation following surgery may be an acceptable form of management in patients with low-risk histologic-type disease.
Abstract
Importance
Salivary gland cancer comprises a diverse group of histologic types with different biological behavior. Owing to this heterogeneity, the association of margin status and postoperative adjuvant radiotherapy has been poorly studied.
Objective
To examine the association between surgical margin status and oncologic outcomes and the subsequent outcome of adjuvant radiotherapy in patients with salivary gland carcinomas.
Design, Setting, and Participants
This cohort study analyzed data from institutional records at Memorial Sloan Kettering Cancer Center from 1985 to 2015. Statistical analysis was completed on October 31, 2020. After exclusions, 837 patients with surgically treated salivary gland carcinoma were identified. Surgical margins and histologic characteristics identified from pathology reports were recorded, with margins classified as negative, close, and positive, and individual histologic types classified into 3 risk groups: low, intermediate, and high.
Exposures
The outcome of adjuvant radiotherapy was determined in patients with close margins with low- and intermediate-risk histologic type and overall pathologic stage I/II disease.
Main Outcomes and Measures
Disease-specific survival (DSS) and local recurrence-free survival (LRFS) outcomes were calculated using the Kaplan-Meier method. Multivariable analysis was performed using the Cox proportional hazards regression model. A planned subgroup analysis of patients with close margins was conducted.
Results
Among the 837 patients identified, 438 were women (52.3%); median age at surgery was 58 years (range, 6-98). A total of 399 tumors (47.7%) originated from major salivary glands, and 438 (52.3%) from minor salivary glands. Margin positivity rates were not different between minor and major salivary gland tumors. Positive surgical margins were identified in 252 patients (30.1%), with nasal cavity/paranasal sinuses and trachea/larynx subsites as the most common sites. Close margins were recorded in 203 patients (24.3%). Adjuvant radiotherapy was administered in 80.5% (103 of 128) of patients with major salivary gland cancer with positive margins, 58.8% (60 of 102) with close margins, and 30.7% (52 of 169) with negative margins and in 70.2% (87 of 124), 36.6% (37 of 101) , and 19.7% (42 of 213) patients with minor salivary gland cancer. With median follow up time of 57 months (range, 1-363 months), patients with positive margins had poorer DSS and LRFS. However, after controlling for overall stage, histologic risk group, and adjuvant radiotherapy, margin status was not a factor associated with poorer DSS or LRFS. In patients with close margins, low-risk and intermediate-risk histologic type, and overall pathologic stage I/II, patients who did not have adjuvant radiotherapy had comparable local control with those who received adjuvant radiotherapy.
Conclusions and Relevance
The findings of this cohort study suggest that patients with salivary gland cancer who have either close or positive surgical margins are at increased risk for poorer local control and survival. After controlling for tumor stage, histologic risk group, and the use of adjuvant radiotherapy, margin status was not an independent factor associated with poorer outcome. Subgroup analyses showed that care for patients with close margins with low-risk or intermediate-risk histologic type who have stage I/II cancers might be managed safely without adjuvant radiotherapy.
This cohort study evaluates the association of surgical margin status with use of postoperative radiotherapy and survival in patients with salivary gland cancer.
Introduction
Salivary gland cancers encompass a highly diverse range of pathologic entities, with more than 20 different histologic presentations listed by the World Health Organization.1 These cancers arise in various anatomic locations, including the major (named) salivary glands and the minor salivary glands in the mucosa of the upper aerodigestive tract. Surgical resection has established efficacy as the primary treatment for salivary gland cancer compared with radiotherapy.2 However, the intrinsic heterogeneity of the histologic types and the variety of anatomic locations has made it challenging to analyze the margins of surgical resection, resulting in a paucity of published literature addressing this issue.3 Salivary gland cancers are often in proximity to or involve crucial anatomic structures, the surgical interruption or sacrifice of which may impart substantial functional or aesthetic morbidity. Because close or positive margins are not uncommon, adjuvant radiotherapy may be indicated in such patients, but this treatment can result in the impairment of salivary function and lead to a negative influence on patients’ quality of life. Thus, we face a clinical dilemma in this group of patients: we must assess the histologic risk of the cancer and its biological behavior on local control and survival and balance this with the beneficial oncologic effects of adjuvant radiotherapy and its subsequent adverse effects.
Postoperative nomograms developed at Memorial Sloan Kettering Cancer Center use histologic risk group, clinical staging, perineural invasion (PNI), regional nodal involvement, and surgical margin status as the variables estimating the probability of local recurrence and survival in salivary gland cancer.4,5 Of these, surgical margin status is the only variable independent of tumor biologic characteristics, and thus, the only significant prognostic factor in which the role of the operating surgeon is crucial. Positive margins have been an acknowledged indication for further treatment. In addition to reoperation, further treatments include radiotherapy with or without chemotherapy, with the understanding that salivary function is most severely affected by these treatment modalities.6,7 Surgical resection with negative margins, when feasible, is the ideal treatment, shown to significantly improve prognosis compared with surgical resection with positive margins.8 Surgical margins labeled close comprise a poorly defined and poorly understood group that may be ambiguous for determining future appropriate management. The aim of our study was to report our experience over a 30-year period in the management of patients with salivary gland cancer and to evaluate the outcome of adjuvant radiotherapy in relation to close surgical margin status on the prognosis of patients with salivary gland cancer.
Methods
Patients
Following approval with a waiver of informed consent owing to deidentified data from the institutional review board at Memorial Sloan Kettering Cancer Center, we analyzed our database of 884 patients with salivary gland cancers, surgically managed from 1985 to 2015, to determine the oncologic outcome of adjuvant radiotherapy in relation to margin status. The cohort of patients included those with minor salivary gland cancers previously reported in a separate study9 but excluded patients with distant metastases at presentation, unknown margin status, or unknown postoperative adjuvant radiotherapy status, resulting in 837 patients for analysis.
Data Collection
Information regarding patient demographic characteristics, clinicopathologic factors, surgical procedure, adjuvant therapy, and oncologic outcomes were recorded. Patient comorbidity status was determined using the Charlson Comorbidity Index.10 The major salivary gland tumors were staged consistently with the 8th edition of the American Joint Committee on Cancer Cancer Staging Manual; minor salivary gland tumors were staged using the same edition’s criteria for mucosal cancers according to the anatomic site of the tumor.11
Definitions
Tumor histologic type was assessed according to the classification for head and neck salivary gland cancers established by the World Health Organization.1 We categorized the more than 20 histologic variants of salivary gland cancer into 3 groups as described previously9,12 using the Kaplan-Meier survival plots for each histologic type and grade. The high-risk group included salivary duct cancer, high-grade myoepithelial cancer, high-grade mucoepidermoid cancer, high-grade carcinoma ex pleomorphic adenoma, high-grade adenoid cystic cancer, high-grade adenocarcinoma, and high-grade acinic cell cancer. The intermediate-risk group consisted of adenoid cystic cancer. The low-risk group included low- and intermediate-grade mucoepidermoid cancer, low-grade acinic cell cancer, low-grade adenocarcinoma, low-grade carcinoma ex pleomorphic adenoma, low-grade myoepithelial cancer, and all polymorphous adenocarcinomas and epithelial-myoepithelial cancers. Margins were classified according to qualitative assessment by the pathologist performing the histopathologic review. A close margin was defined as less than 5 mm for minor salivary gland cancers. In major salivary gland surgery, there is no recognized definition of a close margin. The 5-mm cutoff may be inappropriate because in parotid surgery dissection of tumors from the facial nerve will often result in margins less than 5 mm. At Memorial Sloan Kettering Cancer Center, we have used 1 mm as the cutoff value for close margin. Tumors that have a margin larger than 1 mm are defined as negative margin and margins less than 1 mm defined as close. Owing to the different definitions of a close margin, we have split the data set into major and minor salivary gland cancers and conducted the analysis on each data set.
Statistical Analysis
Oncologic outcomes of interest included overall survival (OS), disease-specific survival (DSS), and local recurrence-free survival (LRFS). Overall survival was calculated from the date of surgery to the date of last follow-up or death. Disease-specific survival was calculated from the date of surgery to the date of last follow-up by a member of the disease management team or death with disease. Local recurrence-free survival was calculated from the date of surgery to the first pathologic findings–confirmed local recurrence or last clinical assessment by the disease management team. Calculations were made in months using the Kaplan-Meier method. Separate analyses were performed for major salivary gland cancers and for minor salivary gland cancers owing to the differences in the definition of a close margin in these 2 groups.
A univariable analysis was performed to determine the frequencies and distribution for all demographic and clinicopathologic variables of the cohort. A bivariable analysis was conducted using the Pearson χ2 or Fisher exact tests when appropriate to examine tumor and adjuvant therapy variables by margin status. Variables were further analyzed by the Kaplan-Meier method and log-rank tests to assess survival. Univariable Cox proportional hazards regression was performed to determine the unadjusted hazard ratio (HR) for each variable. We analyzed factors found to differ significantly between margin status and have an association with survival or be of clinical importance using a multivariable Cox proportional hazards model. Lymphovascular invasion (LVI) and PNI were excluded from the multivariable models owing to confounding outcomes with histologic grade. Overall pathologic stage was used in the model for DSS, whereas pathologic T (pT) category was used in the model for local recurrence.
A planned subgroup analysis examined the use of adjuvant radiotherapy in patients with close margins who lacked other risk factors that would lead to use of adjuvant radiotherapy. Patients with high-risk histologic group status and high overall pathologic stage III/IV cancers were excluded from this analysis. Findings were considered significant at 1-tailed unpaired P < .05. All statistical analyses were conducted using SPSS, version 25.0 (IBM Corp). Data were analyzed on October 31, 2020.
Results
With a median follow up of 57 months (range, 1-363 months), the 5-year OS was 79% and the DSS was 86% for the 837 patients. Four hundred thirty-eight patients (52.3%) were women and 399 patients (47.7%) were men; the median age at the initial surgery was 58 years (range, 6-98), and 444 patients (53.0%) had a Charlson Comorbidity Index score of at least 2 (Table 1). Four hundred eleven patients (49.1%) reported ever using tobacco, and 514 (61.4%) reported ever using alcohol. Four hundred thirty-eight patients (52.3%) had minor salivary gland tumors, and 399 (47.7%) had major salivary gland tumors (347 parotid, 43 submandibular, and 9 sublingual). Pathologic characteristics are also reported in Table 1. The most common histologic types identified were mucoepidermoid cancer (35.8% [300 of 837]) and adenoid cystic cancer (21.1% [177 of 837]). Histologic risk group distribution was as follows: 422 (50.4%) low, 148 (17.7%) intermediate, and 264 (31.5%) high. On pathologic staging, T1 category lesions were identified in 386 patients (46.1%) of the cohort and more advanced tumors (T3-T4) were found in 233 patients (27.8%). Regional lymph nodal metastases were diagnosed in 142 patients (17.0%). Lymphovascular invasion was seen in 129 patients (15.4%), PNI in 303 (36.2%), and extranodal extension in 76 (9.1%). The overall pathologic stages were stage I in 360 patients (43.0%), stage II in 171 (20.4%), stage III in 58 (6.9%), and stage IV in 239 (28.6%).
Table 1. Patient and Pathologic Characteristics.
| Variable | Total, No. (%) |
|---|---|
| No. (%) | 837 (100) |
| Age, y | |
| <60 | 438 (52.3) |
| ≥60 | 399 (47.7) |
| Sex | |
| Male | 399 (47.7) |
| Female | 438 (52.3) |
| Charlson Comorbidity Index score | |
| 0 | 236 (28.2) |
| 1 | 157 (18.8) |
| ≥2 | 444 (53.1) |
| Tobacco use | |
| Never | 390 (46.6) |
| Ever | 411 (49.1) |
| Unknown | 36 (4.3) |
| Alcohol use | |
| Never | 264 (31.5) |
| Ever | 514 (61.4) |
| Unknown | 59 (7.1) |
| Site | |
| Major | 399 (47.7) |
| Minor | 438 (52.3) |
| Site | |
| Major | 399 (47.7) |
| Oral cavity | 297 (35.5) |
| Nasal/paranasal sinus | 36 (4.3) |
| Pharynx | 95 (11.4) |
| Trachea/larynx | 10 (1.2) |
| Histologic group | |
| Mucoepidermoid cancer | 300 (35.8) |
| Adenoid cystic cancer | 177 (21.1) |
| Carcinoma ex pleomorphic adenoma | 65 (7.8) |
| Acinic cell cancer | 63 (7.5) |
| Polymorphous low-grade adenocarcinoma | 56 (6.7) |
| Adenocarcinoma | 54 (6.4) |
| Salivary duct cancer | 36 (4.3) |
| Myoepithelial cancer | 27 (3.2) |
| Epithelial-myoepithelial cancer | 20 (2.4) |
| Other | 39 (4.7) |
| Histologic risk group | |
| Low | 422 (50.4) |
| Intermediate | 148 (17.7) |
| High | 264 (31.5) |
| Unknown | 3 (0.4) |
| Pathologic T category | |
| TX | 9 (1.1) |
| T1 | 386 (46.1) |
| T2 | 209 (25.0) |
| T3 | 52 (6.2) |
| T4 | 181 (21.6) |
| Pathologic N category | |
| N0/NX | 695 (83.0) |
| N1 | 31 (3.7) |
| N2 | 109 (13.0) |
| N3 | 2 (0.2) |
| AJCC stage (8th edition) | |
| I | 360 (43.0) |
| II | 171 (20.4) |
| III | 58 (6.9) |
| IV | 239 (28.6) |
| Unknown | 9 (1.1) |
| Lymphovascular invasion | |
| No | 458 (54.7) |
| Yes | 129 (15.4) |
| Unknown | 250 (29.9) |
| Perineural invasion | |
| No | 319 (38.1) |
| Yes | 303 (36.2) |
| Unknown | 215 (25.7) |
| Extranodal extension | |
| No | 591 (70.6) |
| Yes | 76 (9.1) |
| Unknown | 170 (20.3) |
| Margins | |
| Negative | 382 (45.6) |
| Close | 203 (24.3) |
| Positive | 252 (30.1) |
| Adjuvant treatment | |
| None | 456 (54.5) |
| Adjuvant radiotherapy | 340 (40.6) |
| CRT | 41 (4.9) |
Abbreviations: AJCC, American Joint Committee on Cancer; CRT, chemoradiotherapy.
Positive surgical margins were identified in nearly a third of the patients (252 [30.1%]), 382 patients (45.6%) had negative margins, and 203 (24.3%) had close margins. Surgery alone was used to treat 456 patients (54.5%), and 340 (40.6%) required adjuvant radiotherapy. Another 41 patients (49.0%) received adjuvant radiotherapy in combination with systemic therapy. Indications for adjuvant radiotherapy were the presence of high-risk-features, which included high-risk histologic group, pathologic T3/T4 category primary tumors, positive neck nodes, high overall pathologic stage III/IV, and positive margins. Patients received adjuvant radiotherapy at a median dosage of 62 Gy (range, 50-70 Gy).
Distribution by Margin Status
Pathologic and treatment variables stratified by margin status for major and minor salivary gland cancers are presented in Table 2. Rates of margin positivity were not different between major and minor salivary gland tumors (128 [32.1%] vs 124 [28.3%]; P = .19). For major salivary gland tumors, 55 (57.3%) of the 96 patients with pT4 category, 43 (56.6%) of 76 patients with nodal metastases (pN+), and 67 (40.6%) of 165 patients with a high-risk histologic group had positive margins. Of 144 patients with perineural invasion, 69 (47.9%) had positive margins. Negative margins were noted in 98 (51.0%) of 192 patients with a low-risk histologic group, 80 (55.2%) of 145 patients with pT1, and 151 (46.7%) of 323 patients with pN0. Adjuvant radiotherapy was administered in 30.7% (52 of 169) of patients with negative margins, compared with 58.8% (60 of 102) of those with close margins and 80.5% (103 of 128) of those with positive margins (P < .001). Reasons for 25 patients with positive margins not receiving adjuvant radiotherapy included low-risk pathologic category, surgeon and patient preference for intermediate-risk pathologic category, and patient refusal.
Table 2. Pathologic and Treatment Variables Stratified by Margin.
| Variable | No. (%) | P value | ||
|---|---|---|---|---|
| Negative | Close | Positive | ||
| Major salivary gland cancer | ||||
| No. (%) | 169 (42.4) | 102 (25.6) | 128 (32.1) | |
| Site | ||||
| Major | 169 (42.4) | 102 (25.6) | 128 (32.1) | <.001 |
| Histologic risk group | ||||
| Low | 98 (51) | 48 (25) | 46 (24) | .003 |
| Intermediate | 13 (31) | 14 (33.3) | 15 (35.7) | |
| High | 58 (35.2) | 40 (24.2) | 67 (40.6) | |
| Perineural invasion | ||||
| No | 107 (54.3) | 49 (24.9) | 41 (20.8) | <.001 |
| Yes | 34 (23.6) | 41 (28.8) | 69 (47.9) | |
| Unknown | 28 (48.3) | 12 (20.7) | 18 (31) | |
| Lymphovascular invasion | ||||
| No | 120 (47.8) | 61 (24.3) | 70 (27.9) | .01 |
| Yes | 20 (25.6) | 24 (30.8) | 34 (43.6) | |
| Unknown | 29 (41.4) | 17 (24.3) | 24 (34.3) | |
| Pathologic T category | ||||
| T1 | 80 (55.2) | 38 (26.2) | 27 (18.6) | <.001 |
| T2 | 53 (45.3) | 31 (26.5) | 33 (28.2) | |
| T3 | 9 (26.5) | 13 (38.2) | 12 (35.3) | |
| T4 | 21 (21.9) | 20 (20.8) | 56 (5.3) | |
| Pathologic N status | ||||
| N–/Nx | 151 (46.8) | 87 (26.9) | 85 (26.3) | <.001 |
| N+ | 18 (23.7) | 15 (19.7) | 43 (56.6) | |
| AJCC stage (8th edition) | ||||
| I | 79 (55.6) | 38 (26.8) | 25 (17.6) | <.001 |
| II | 49 (49.5) | 25 (25.3) | 25 (25.3) | |
| III | 6 (22.2) | 12 (44.4) | 9 (33.3) | |
| IV | 29 (23.4) | 27 (21.8) | 68 (54.8) | |
| Postoperative radiotherapy | ||||
| No | 117 (63.6) | 42 (22.8) | 25 (13.6) | <.001 |
| Yes | 52 (24.2) | 60 (27.9) | 103 (47.9) | |
| Minor salivary gland cancer | ||||
| No. (%) | 213 (48.6) | 101 (23.1) | 124 (28.3) | |
| Site | ||||
| Minor | 213 (48.6) | 101 (23.1) | 124 (28.3) | .002 |
| Site subcategory | ||||
| Oral cavity | 152 (51.2) | 67 (22.6) | 78 (26.3) | |
| Nasal/paranasal sinus | 11 (30.6) | 4 (11.1) | 21 (58.3) | |
| Pharynx | 46 (48.4) | 29 (30.5) | 20 (21.1) | |
| Trachea/larynx | 4 (40) | 1 (10) | 5 (50) | |
| Histologic risk group | ||||
| Low | 142 (61.7) | 53 (23.0) | 35 (15.2) | <.001 |
| Intermediate | 24 (22.6) | 26 (24.5) | 56 (52.8) | |
| High | 44 (44.4) | 22 (22.2) | 33 (33.3) | |
| Perineural invasion | ||||
| No | 61 (50) | 36 (29.5) | 25 (20.5) | <.001 |
| Yes | 41 (25.8) | 43 (27) | 75 (47.2) | |
| Unknown | 111 (70.7) | 22 (14) | 24 (15.3) | |
| Lymphovascular invasion | ||||
| No | 87 (42) | 56 (27.1) | 64 (31) | <.001 |
| Yes | 10 (19.6) | 14 (27.5) | 27 (53) | |
| Unknown | 116 (64.4) | 31 (17.2) | 33 (18.3) | |
| Pathologic T category | ||||
| T1 | 147 (61) | 57 (23.7) | 37 (15.4) | <.001 |
| T2 | 38 (41.3) | 26 (28.3) | 28 (30.4) | |
| T3 | 8 (44.4) | 4 (22.2) | 6 (33.3) | |
| T4 | 19 (22.4) | 14 (16.5) | 52 (61.2) | |
| Pathologic N status | ||||
| N–/Nx | 183 (49.2) | 87 (23.4) | 102 (27.4) | .62 |
| N+ | 30 (45.5) | 14 (21.2) | 22 (33.3) | |
| AJCC stage (8th edition) | ||||
| I | 131 (60.1) | 56 (25.7) | 31 (14.2) | <.001 |
| II | 32 (44.4) | 20 (27.8) | 20 (27.8) | |
| III | 16 (51.6) | 5 (16.1) | 10 (32.3) | |
| IV | 33 (28.7) | 20 (17.4) | 62 (53.9) | |
| Postoperative radiotherapy | ||||
| No | 171 (62.9) | 64 (23.5) | 37 (13.6) | <.001 |
| Yes | 42 (25.3) | 37 (22.3) | 87 (52.4) | |
Abbreviation: AJCC, American Joint Committee on Cancer.
For minor salivary gland tumors, the subsites most susceptible to margin involvement were the nasal/paranasal sinuses (n = 36), with 21 (58.3%) having positive margins, and the trachea/larynx (n = 10), with 5 (50.0%) having positive margins. All other factors differed significantly between the margin groups. Of note, 52 (61.2%) of 85 patients with pT4 category (P < .001), 22 (33.3%) of 66 patients with nodal metastases (pN+), and 33 (33.3%) of 99 patients with the high-risk histologic group (P < .001) had positive margins. Perineural invasion was identified in 75 (47.2%) of 159 patients with positive margins; 142 (61.7%) of 230 patients with a low-risk histologic group, 147 (61.0%) of 241 patients with pT1 category, 183 (49.2%) of 372 patients with pN0–, 152 (51.2%) of 297 patients with oral cavity, and 46 (48.4%) of 95 patients with pharynx tumors had negative margins. Of 166 patients who received adjuvant radiotherapy, 25.3% had negative margins, compared with 22.3% of those with close margins and 52.4% of those with positive margins (P < .001). Reasons for 37 patients (13.6%) with positive margins not receiving adjuvant radiotherapy included low-risk pathologic category, surgeon and patient preference for intermediate-risk pathologic category, and patient refusal.
Margin Status and DSS
For major salivary gland tumors, the 5-year DSS of patients with negative margins was 85.0%; close margins, 70.0%; and positive margins, 63.5% (Figure 1A). Patients with positive margins had a 2.7-fold increased risk of disease-specific death (HR, 2.69; 95% CI, 1.53-4.77) compared with patients who had negative margins (Table 3). Patients with close margins had a 1.8-fold increased risk of disease-specific death (HR, 1.84; 95% CI, 0.97-3.48). Other factors associated with DSS were histologic risk group, overall pathologic stage, and use of adjuvant radiotherapy. After adjusting for these factors, margin status was not significant. Histologic risk group was the only independent factor associated with DSS.
Figure 1. Margin Status and Disease-Specific Survival for Patients With Salivary Gland (SG) Cancer.
A, Disease-specific survival stratified by margin status for major SG cancer. B, Local recurrence-free survival stratified by margin status for major SG cancer. C, Disease-specific survival stratified by margin status for minor SG cancer. D, Local recurrence-free survival stratified by margin status for minor SG cancer.
Table 3. Univariable and Multivariable Analysis of Margin Status on Disease-Specific Survival and Margin Status on Local Recurrence-Free Survival.
| Factor | Margin status on DSS | Margin status on LRFS | ||||
|---|---|---|---|---|---|---|
| 5-y DSS | HR (95% CI) | 5-y LRFS | HR (95% CI) | |||
| Univariable | Multivariable | Univariable | Multivariable | |||
| Major salivary gland cancer | ||||||
| Margin | ||||||
| Negative | 85.3 | 1 [Reference] | 1 [Reference] | 94.1 | 1 [Reference] | 1 [Reference] |
| Close | 70.1 | 1.84 (0.97-3.48) | 1.37 (0.70-2.65) | 89.6 | 1.43 (0.48-4.25) | 1.34 (0.41-4.41) |
| Positive | 63.5 | 2.69 (1.53-4.77) | 1.43 (0.77-2.63) | 74.8 | 4.08 (1.74-9.61) | 3.30 (1.19-9.13) |
| Site | ||||||
| Major | 74.5 | 2.76 (1.91-3.99) | NA | 88.6 | 1.44 (0.89-2.30) | NA |
| Histologic risk group | ||||||
| Low | 97.1 | 1 [Reference] | 1 [Reference] | 96.1 | 1 [Reference] | 1 [Reference] |
| Intermediate | 91.1 | 6.62 (1.58-27.70) | 4.81 (1.10-20.99) | 77.6 | 7.24 (2.12-24.72) | 6.97 (1.89-25.67) |
| High | 46.3 | 32.17 (10.10-102.49) | 13.59 (3.86-47.91) | 78.1 | 7.85 (2.71-22.72) | 5.66 (1.67-18.90) |
| AJCC pathologic stage (8th edition) | NA | NA | NA | |||
| I | 100 | 0 | 0 | NA | NA | NA |
| II | 82.6 | 1 [Reference] | 1 [Reference] | NA | NA | NA |
| III | 74.2 | 1.81 (0.63-5.23) | 1.01 (0.35-2.97) | NA | NA | NA |
| IV | 45.3 | 4.88 (2.54-9.36) | 1.77 (0.85-3.71) | NA | NA | NA |
| pT category | NA | NA | NA | |||
| T1 | NA | NA | NA | 97 | 1 [Reference] | 1 [Reference] |
| T2 | NA | NA | NA | 90.8 | 3.08 (0.80-11.91) | 2.67 (0.68-10.59) |
| T3 | NA | NA | NA | 66.9 | 9.18 (2.29-36.74) | 4.93 (1.14-21.28) |
| T4 | NA | NA | NA | 73.2 | 9.43 (2.74-32.38) | 5.13 (1.27-20.65) |
| Adjuvant radiotherapy | ||||||
| No | 95.4 | 1 [Reference] | 1 [Reference] | 92.6 | 1 [Reference] | 1 [Reference] |
| Yes | 63 | 9.79 (3.95-24.29) | 0.90 (0.32-2.50) | 82.5 | 2.27 (1.03-5.01) | 0.34 (0.13-0.89) |
| Minor salivary gland cancer | ||||||
| Margin | ||||||
| Negative | 95.5 | 1 [Reference] | 1 [Reference] | 94.3 | 1 [Reference] | 1 [Reference] |
| Close | 91.4 | 1.84 (0.84-4.03) | 1.66 (0.69-4.00) | 89.4 | 2.63 (1.11-6.23) | 2.50 (0.96-6.51) |
| Positive | 92.7 | 2.38 (1.26-4.52) | 1.49 (0.63-3.55) | 87.2 | 2.93 (1.37-6.72) | 1.83 (0.66-5.08) |
| Site | ||||||
| Oral cavity | 95.3 | 1 [Reference] | 1 [Reference] | 95.7 | 1 [Reference] | 1 [Reference] |
| Sinus | 88.8 | 2.70 (1.21-6.04) | 0.59 (0.25-1.41) | 70.2 | 6.56 (3.11-13.84) | 1.76 (0.73-4.26) |
| Pharynx | 91.4 | 2.08 (1.08-3.99) | 1.07 (0.51-2.26) | 90.1 | 1.53 (0.66-3.55) | 1.02 (0.40-2.59) |
| Trachea/larynx | 100.0 | 2.17 (0.51-9.23) | 0.41 (0.09-1.81) | 100.0 | 1.66 (0.22-12.48) | 0.40 (0.05-3.16) |
| Histologic risk group | ||||||
| Low | 98.9 | 1 [Reference] | 1 [Reference] | 97.1 | 1 [Reference] | 1 [Reference] |
| Intermediate | 98.7 | 7.85 (2.91-21.15) | 2.26 (0.72-7.09) | 91.8 | 4.89 (1.86-12.86) | 1.95 (0.62-6.08) |
| High | 77.1 | 14.44 (5.52-37.73) | 7.06 (2.51-19.83) | 79.2 | 9.59 (3.83-24.03) | 5.77 (2.06-16.17) |
| AJCC pathologic stage (8th edition) | NA | NA | NA | |||
| I | 98 | 1 [Reference] | 1 [Reference] | NA | NA | NA |
| II | 95.4 | 7.29 (1.82-29.21) | 6.04 (1.41-25.92) | NA | NA | NA |
| III | 89.3 | 30.91 (8.61-110.93) | 34.57 (8.33-143.53) | NA | NA | NA |
| IV | 84.4 | 24.66 (7.49-81.23) | 15.89 (4.18-60.47) | NA | NA | NA |
| pT category | NA | NA | NA | |||
| T1 | NA | NA | NA | 97.9 | 1 [Reference] | 1 [Reference] |
| T2 | NA | NA | NA | 91.3 | 5.02 (1.64-15.41) | 4.96 (1.48-16.62) |
| T3 | NA | NA | NA | 69.2 | 18.38 (5.28-64.01) | 20.64 (4.54-93.96) |
| T4 | NA | NA | NA | 79.3 | 14.06 (5.27-27.52) | 12.65 (4.02-39.77) |
| Adjuvant radiotherapy | ||||||
| No | 96.1 | 1 [Reference] | 1 [Reference] | 94.4 | 1 [Reference] | 1 [Reference] |
| Yes | 90.8 | 5.56 (2.83-10.90) | 0.82 (0.33-2.05) | 89.1 | 3.05 (1.56-5.97) | 0.37 (0.14-1.01) |
Abbreviations: AJCC, American Joint Committee on Cancer; DSS, disease-specific survival; HR, hazard ratio; LRFS, local recurrence-free survival; NA, not applicable; pT, pathologic tumor.
For minor salivary gland tumors, the 5-year DSS of patients with negative margins was 95.5%; close margins, 91.4%; and positive margins, 92.7% (Figure 1B). Patients with positive margins had a 2.4-fold increased risk of disease-specific death (HR, 2.38; 95% CI, 1.26-4.52) compared with patients with negative margins (Table 3). Patients with close margins had a 1.8-fold increased risk of disease-specific death (HR, 1.84; 95% CI, 0.84-4.03). Other factors associated with DSS were tumor subsite, histologic risk group, overall pathologic category, and use of adjuvant radiotherapy. After adjusting for these factors, margin status was not significant. Histologic risk group and overall pathologic category were the only independent factors associated with DSS.
Margin Status and LRFS
For major salivary glands, the 5-year LRFS for negative margins was 94.1%; close margins, 89.6%; and positive margins, 74.8% (Figure 1C). Close margins had a 1.43-fold increased risk of local recurrence (HR, 1.43; 95% CI, 0.48-4.25), and positive margins had a 4.01-fold increased risk compared with negative margins (HR, 4.08; 95% CI, 1.74-9.61) (Table 3). Histologic risk group, pT category, and adjuvant radiotherapy were all significant on univariable analysis for LRFS. After adjusting for these variables and for subsite, positive margin status remained an independent factor associated with local disease recurrence (HR, 3.30; 95% CI, 1.19-9.13). Although the finding was not statistically significant, patients with close margins had a 1.34-fold increased risk of local recurrence compared with those with negative margins (HR, 1.34; 95% CI, 0.41-4.410). Adjuvant radiotherapy also remained a significant independent estimator in multivariable analysis, with patients receiving adjuvant radiotherapy having improved local control (HR, 0.34; 95% CI, 0.13-0.89).
For minor salivary glands, the 5-year LRFS for negative margins was 94.3%; close margins, 89.4%; and positive margins, 87.2% (Figure 1D). Close margins had a 2.63-fold increased risk of local recurrence (HR, 2.63; 95% CI, 1.11-6.23), and positive margins had a 2.93-fold increased risk compared with negative margins (HR, 2.93; 95% CI, 1.37-6.72) (Table 3). Tumor subsite, histologic risk group, pT category, and adjuvant radiotherapy were all significant on univariable analysis for LRFS. After adjusting for these variables and for subsite, margin status was no longer significant. Histologic risk group, pathologic T category, and use of adjuvant radiotherapy remained significant independent factors in multivariable analysis. Patients receiving adjuvant radiotherapy had improved local control (HR, 0.37; 95% CI, 0.14-1.00).
Adjuvant Radiotherapy and Local Control in the Close Margin Group
Indications for adjuvant radiotherapy are high-risk features, such as positive margins, high-grade histologic group, and high stage III/IV disease. In patients with close margins who have low stage I/II disease and are in the low/intermediate-risk histologic group, the role of adjuvant radiotherapy is controversial. We therefore conducted a subgroup analysis of these patients. Of the 203 individuals who had close margins, 118 (58.1%) were in the low-risk or intermediate-risk histologic group and stage I/II had cancer. In the low-risk histologic group (n = 90), 19 patients (21.1%) received adjuvant radiotherapy. There were only 2 patients who experienced a local recurrence during the follow-up interval: 1 in the adjuvant radiotherapy group and 1 in the no adjuvant radiotherapy group. In the intermediate-risk histologic group (n = 28), all patients had adenoid cystic cancer. Sixteen patients (57.1%) received adjuvant radiotherapy, of whom 13 had perineural invasion in addition to close margins. There were only 2 patients who experienced a local recurrence during the follow-up interval, and neither received adjuvant radiotherapy (1 patient had PNI and 1 did not). Univariable analysis showed that tumor site, histologic risk group, overall stage, and adjuvant radiotherapy were not factors associated with LRFS (eTable 1 in the Supplement). In particular, adjuvant radiotherapy was not associated with improved local control (HR, 0.66; 95% CI, 0.07-6.34). In the low-risk histologic group, patients who did not receive adjuvant radiotherapy had local control similar to that of patients who received adjuvant radiotherapy (Figure 2A). In addition, in the intermediate-risk histologic group, patients who did not receive adjuvant radiotherapy had local control similar to that of those who received adjuvant radiotherapy (Figure 2B).
Figure 2. Local Recurrence-Free Survival Stratified by Postoperative Radiation for Low- and Intermediate-Risk Histologic Groups With Close Margins.
Low-risk (A) and intermediate-risk (B) groups.
Outcome of Patients With Positive Margins Without Adjuvant Radiotherapy
Sixty-two patients who had positive margins did not receive adjuvant radiotherapy. Patient and pathologic characteristics are reported in eTable 2 in the Supplement. Of these, 38 patients (61.3%) were in the low-risk; 6 (9.7%), intermediate-risk; and 18 (29.0%), high-risk histologic group. Most patients had T1/T2 tumors (45 [72.6%]) with N0/Nx (59 [95.2%]) category. In 62 patients, there were 8 local recurrences, 4 distant recurrences, and 5 regional recurrences. Outcomes are presented in eTable 3 in the Supplement. Overall, patients had a DSS of 79.8% and LRFS of 77.8%. Patients in the low-risk histologic group had a 10-year DSS of 100% and 88.6% local control. Patients with stage I/II disease had a 10-year DSS of 100%. In contrast, poor survival was noted in patients in the high-risk histologic group (10-year DSS, 30%) or with stage III (10-year DSS, 50%) disease.
Discussion
The objective of this study was to report the association between surgical margin status and oncologic outcomes and the subsequent association with adjuvant radiotherapy in patients with salivary gland cancers. We used a large single-institution database comprising 837 patients with diverse histologic type and tumor locations to study this topic. As has been reported in other studies,4,5,6,7,9,12,13 the results of our analysis suggest that overall stage and histologic risk group remain the 2 most important factors that estimate the outcome in patients with salivary gland cancer. We noted that patients who have positive margins at surgery show much poorer outcomes compared with those who have negative-margin resections.13 However, after controlling for tumor stage, histologic risk group, and the use of adjuvant radiotherapy, margin status was not an independent indicator of poorer outcome.
As expected, we noted that positive margins are more common in patients who have cancer of the major salivary glands, larger T category (T3-T4) tumors, and high-risk pathologic disease. For the most represented gland (parotid gland), the facial nerve may limit the margin that can be obtained because the facial nerve often abuts the tumor.14 This relationship of the facial nerve to the tumor accounts for why positive margins are more common in this site. In addition, although the minor salivary glands are usually visible on mucosal surfaces, their propensity toward the small spaces of the aerodigestive tract, such as the larynx or sinonasal cavity, restricts access and makes the attempt at negative margin resection difficult without substantial morbidity. Thus, positive margins are also more common in minor salivary gland tumors located in the sinuses, trachea, and larynx. With regard to high-risk tumor histologic type and grade, other high-risk pathologic features, such as PNI and LVI, are common. It is therefore not surprising that these patients also show a higher probability of having a positive margin on surgical resection.
Salivary gland cancers have heterogeneous pathologic characteristics, with more than 20 different types. Owing to this diverse range of histologic factors and behavior, it is very difficult to analyze individual pathologic findings on the association of margin status with local control. We grouped the histologic types in our study into 3 different risk categories—low, intermediate, and high—as reported previously.9,12 As expected, patients with high-risk and intermediate-risk pathologic factors were more likely to have positive margins, whereas patients with low-risk pathology were more likely to have negative margins. Patients with positive margins required adjuvant radiotherapy, whereas patients with negative margins did not always require adjuvant radiotherapy. We performed a subgroup analysis in the patients with close margins who had low- or intermediate-risk pathologic status and who had low stage I/II disease because this is a group for which the decision to treat with adjuvant radiotherapy is controversial.15,16 In the low-risk histologic group, patients who did not receive adjuvant radiotherapy had comparable local control with those who received adjuvant radiotherapy, suggesting that, in the low-risk histologic group, close margins may not necessarily be an indication for adjuvant radiotherapy. Of the 90 patients with stage I/II disease in the low-risk histologic group, there were only 2 local recurrences—1 in the no adjuvant radiotherapy group and 1 in the adjuvant radiotherapy group—with no patients dying from their disease during follow-up. It may therefore be reasonable to consider avoiding radiotherapy in this patient group with an otherwise excellent prognosis, which would improve quality of life by minimizing the toxic effects that radiation imparts on the host’s salivary tissue.17,18 In this study, there were 62 patients with positive margins who did not receive adjuvant radiotherapy, mainly owing to patient refusal. Of these patients, 61% had a low-risk histologic group, all of whom had a 100% survival and a local control rate of 89%. Thus, the use of adjuvant radiotherapy in patients with positive margins who have a low-risk histologic group and low stage I/II disease is controversial based on our data.
Although defining margin adequacy in the low-risk histologic group may aid in avoiding unnecessary treatments, high-risk pathologic margin status has an association with overall prognosis. The aggressive biological behavior of these entities manifests in both poorer DSS and LRFS.19 Given the significant improvement in local control and survival that negative-margin resection has in patients with major salivary gland cancers, the possible sacrifice of important contiguous anatomic structures, such as the facial nerve, may be worth considering.20 Appropriate preoperative counseling of these patients should include not only prognostic variables but also address the morbidity each individual patient deems acceptable in the pursuit of optimizing oncologic and survival outcomes.
Established management paradigms have questioned the efficacy of radiotherapy as a primary treatment modality for salivary gland cancers.21 Xerostomia and mucositis are the 2 most common adverse effects of radiotherapy negatively affecting the quality of life of patients with head and neck cancer; the metabolically active salivary tissue is most susceptible to damage and dysfunction from this treatment.22,23 Balanced against these complicating factors, our analysis shows improved rates of local control with adjuvant radiotherapy in both major and minor salivary gland cancers. In patients with intermediate- and high-risk histologic groups, the presence of other negative variables, such as LVI, PNI, and advanced pT category, may also indicate a need for adjuvant radiotherapy. Therefore, most of these patients will benefit from adjuvant radiotherapy. Even though high-grade pathologic disease has a propensity for distant metastases,24 the control of locoregional disease remains paramount.25
Limitations
There are limitations to our study related to the biases associated with retrospective data collection. The rarity of this disease requires a long time to collect an adequate number of cases; therefore, misclassification bias is possible. Despite this limitation, this large cohort of patients reports comprehensive details on clinical, pathologic, and treatment characteristics as well as outcome information collected from an institution with decades of experience in the multidisciplinary management of salivary gland malignant neoplasms.
Conclusions
Salivary gland cancers are rare, with primary surgical resection forming the mainstay of treatment. The wide diversity of pathologic characteristics and tumor sites makes it difficult to define what constitutes an ideal oncologic surgical margin. There is subsequent clinical ambiguity in the salivary cancer management paradigm, particularly with respect to patients with close margins. Appreciation of tumor biologic factors remains fundamental for both prognostication and the application of adjuvant treatment. In this single-center cohort study of patients with surgically treated salivary gland cancers, we report that patients with close and positive margins have poorer local control and survival compared with patients with negative margins. This difference was particularly pronounced in patients with major salivary gland cancers. However, after controlling for tumor stage, histologic risk group and the use of adjuvant radiotherapy, margin status did not appear to be an independent factor associated with poorer outcome. Among patients with close margins who have a low-risk histologic group and low-stage I/II disease, local control in patients who did not receive adjuvant radiotherapy was comparable to the control achieved in those who received adjuvant radiotherapy. Observation may be a safe postoperative course in patients with close margins who have a low-risk histologic group and low-stage disease.
eTable 1. Factors Predictive of LRFS in Close Margin Patients With Low/Intermediate Risk Pathology and Low Stage Disease
eTable 2. Patient and Pathology Characteristics of Patients With Positive Margins Who Did Not Have PORT
eTable 3. Outcomes of Patients With Positive Margins Who Did Not Have PORT
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Factors Predictive of LRFS in Close Margin Patients With Low/Intermediate Risk Pathology and Low Stage Disease
eTable 2. Patient and Pathology Characteristics of Patients With Positive Margins Who Did Not Have PORT
eTable 3. Outcomes of Patients With Positive Margins Who Did Not Have PORT