The effects of adjuvant radiotherapy on survival outcomes in polymorphous adenocarcinoma: a retrospective cohort study

Introduction

Polymorphous adenocarcinoma (PAC), formerly termed polymorphous low-grade adenocarcinoma before aggressive subtypes were identified, is the second most common malignant tumor of the minor salivary glands (1,2). The most common sites for primary PAC tumors are the minor salivary glands, specifically the palate and buccal mucosa. The major salivary glands (submandibular, sublingual, or parotid) are less commonly affected and comprise a small subset of total PAC cases (3). Pathologically, PAC is an infiltrative, unencapsulated salivary gland tumor (SGT) that demonstrates a highly variable architecture of monomorphic cells around nerves and vessels (2). Differentiation from other SGTs can be complex, but the PRKD1 E710D hotspot mutation and several immunomarkers are associated with PAC [S100 (+)/CK7 (+)/p63 (+)/p40 (−)] (2).

PAC is typically diagnosed in the 6^th to 7^th decade of life (50–70 years) and presents as painless mucosal swelling with possible ulceration, but may also present asymptomatically and be found incidentally (2,4-6). Tumors found incidentally are often discovered during dental appointments, most often for denture resizing or routine evaluations (7). The disease is more common in women (2:1 ratio), and incidence may be higher in black patient populations (6,7). PAC presents indolently, though some histologic subtypes exhibit aggressive behavior and are associated with higher rates of lymph node metastasis (8). Average primary tumor size at the time of diagnosis is 2.2 cm, with a range of 0.4–6 cm (7).

The prognosis of PAC is favorable, with a 10-year disease-specific survival (DSS) of 94–99% (2,9,10). Metastasis occurs in 3–4% of cases, and is often secondary to aggressive subtypes of PAC, which may demonstrate late distant recurrences (2). High-risk histologic features include ≥10% papillary or ≥30% cribriform architecture and correlate with worse survival outcomes (2,11). Positive margin status after resection is a negative prognostic factor, though some studies have demonstrated that margin status is not associated with effects on prognosis (12,13).

The standard of treatment for PAC is surgical resection, and in some cases, adjuvant radiation therapy (RT) with or without neck dissection (4,6,14). The use of adjuvant RT is currently reserved for high-risk cases, including those with incomplete resection, positive margins, perineural invasion, and nodal metastasis, with variable reported effects on overall survival (OS) (2,15). Previous investigations of adjuvant RT for patients with PAC and positive margins demonstrated positive effects on OS in a sizable cohort analyzed from 2004 to 2016 (13). The low prevalence of PAC poses challenges to the feasibility of prospective investigation of the survival benefits of adjuvant RT, and makes the utilization of retrospective data a viable option for literature contributions (16).

To address these gaps in the literature, we conducted a large-scale retrospective review of patients registered within the National Cancer Database (NCDB) treated for PAC between 2004 and 2020 to (I) provide insight into the current epidemiologic features of PAC and (II) report on the survival benefit of RT in a population of otherwise healthy patients with PAC and positive resection margins. The NCDB was chosen for its ability to generate a large cohort and thus allow for properly powered statistical results. Of note, the NCDB lacks several key data fields, including DSS. These omitted fields resulted in data analysis alterations, like the use of OS as a surrogate for DSS. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1760/rc).

Methods

The NCDB was queried for all cases of low-grade PAC via International Classification of Diseases for Oncology, Third Revision (ICD-O-3) (code 8525) from 2004 to 2020 (1). The NCDB is a publicly available and deidentified database, and thus, institutional review board approval was not required. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The database includes patient data from ~1,500 national CoC-accredited institutions (Commission on Cancer) and reports upon approximately 70% of new cancer cases in the United States.

The Charlson-Deyo (CD) index, a validated tool for quantification of medical comorbidities, was utilized to identify patients with comorbidities (17). The CD index assesses the overall health status of patients via measurement of 19 comorbidities and is an independent predictor of survival outcomes in certain cancer patient populations, specifically bladder cancer (17,18).

Inclusion criteria included cancer of the head and neck diagnosed from 2004 to 2020 and complete data fields for the following variables: staging, margin status, follow-up, and survival outcomes (OS). Of note, certain data fields, specifically follow-up, were coded as simple “yes” (=1) or “no” (=0) for data analysis purposes. This approach was chosen based on dataset limitations, specifically the absence of detailed information on follow-up practices and timelines available in the dataset, and the assumption that follow-up varies across institutions. Individuals with missing data for any of the aforementioned variables were excluded to strengthen dataset integrity and limit the effects of measurement vias through the data extraction process.

Patients with CD index scores >0 were excluded to limit the confounding effects of overall health status and allow for the investigation of the role of adjuvant RT in an otherwise healthy population of patients with PAC and positive margins post-surgical resection. The exclusion of patients with missing data fields and the decision to code certain variables, including follow-up, in a binary manner, were made to limit measurement bias effects on data analysis (1).

Descriptive variables included age (coded in quartiles: <50, 50–60, 60–70, and >70 years), sex (male, female), race (White, Black, Asian, other), and insurance status (government-sponsored, private insurance, or uninsured/unknown), anatomic site (major gland, minor gland), major gland subtype (parotid, submandibular, sublingual), tumor staging (T staging), nodal disease (negative, positive), surgery, margin status, adjuvant RT, chemotherapy, and DSS and OS, both measured in months.

Clinical characteristics captured include primary site, T staging, nodal staging (N staging), treatment, and timing of treatment. Of note, the NCDB reports combined staging (pathological over clinical), which is specific to the American Joint Committee on Cancer (AJCC) version in effect at the time of diagnosis (19). Thus, this project contains an expected mixture of AJCC 6^th–8^th staging reporting. Patients with noninvasive disease (i.e., T0) at diagnosis and those without staging, survival, or follow-up data were also excluded from the cohort. Margin status was assessed in all registered surgical specimens, and variables were coded to capture discrete treatment cohorts. Margins were documented within the RX_SUMM_SURGICAL_MARGINS field in the NCDB. In this study, 1, 2, 3 were grouped as positive margins, and 7, 8, 9 as indeterminate/not available. 0 is negative. Patients with tumor and nodal stage were re-coded for ease of analysis, with the pathologic stage being used, when possible.

Statistical analysis

Descriptive, univariable, multivariable, and survival analysis (adjusted for sex, facility type, race, insurance payor, tumor stage, nodal stage, margin status, grade, salivary gland type, RT, and chemotherapy) was performed in R version 4.3.1. Patient demographic and clinical characteristics, treatment modalities, and OS were evaluated across all subsites of the head and neck and then limited to the most frequent sites. Analyses were stratified by major vs. minor salivary gland site, grade, T staging, and treatment modality. Significance was assessed with a 95% confidence interval (CI).

Results

Descriptive statistics

A total of 1,292 patients were included [age: <50 years, 305 (23.6%); 50–60 years, 343 (26.6%); 60–70 years, 370 (26.7%); >70 years, 272 (21.1%); 412 males (31.9%) and 878 females (68.1%); 927 White (71.9%), 300 Black (23.3%), 16 Asian (1.2%), 40 other (3.6%)] with PAC were included in this retrospective study. Full descriptive characteristics can be found in Table 1. Detailed information on final cohort selection is included in Figure 1. Patients aged >70 years composed 31.0% of the study population, but accounted for 15.6% of patients receiving adjuvant therapy (<50 years, 26.4%; 50–60 years, 26.8%; and 60–70 years, 31.1%). Government insurance was reported for 577 patients (44.7%), and private insurance was reported for 646 cases (50.1%). An insurance payor was not available for 67 patients (5.2%).

Figure 1 Patient selection methodology with preliminary dataset numbers and final cohort size. ICD-O-3, International Classification of Diseases for Oncology, Third Revision; NCDB, National Cancer Database; T stage, tumor stage.

Tumor characteristics and treatment modalities

All patients were treated with surgical excision. The majority, 1,035 (80.0%), underwent surgical resection alone, 238 (19.9%) underwent surgical resection followed by adjuvant RT, and 19 (1.5%) were treated with resection, radiation, and chemotherapy (Table 2). Nine hundred tumors demonstrated low-grade (69.8%) pathology, and high-grade characteristics were cited in 9 cases (0.7%); unknown or unreported (16.9%) (Table 2). The majority of patients presented with early-stage (T1–2) disease (80.2% T1–2 vs. 19.8% T3–4). Notably, 73 (5.7%) had nodal disease. Negative surgical margins were achieved in 1,012 patients (78.4%). Of those with positive margins, 86 (30.9%) received adjuvant RT, and 5 (1.8%) received adjuvant RT and chemotherapy. Adjuvant therapy was administered in 71.2% of patients with nodal disease.

OS

Cohort members aged <50 years demonstrated greater OS compared to those 50 years and older [50–60 years, hazard ratio (HR) =2.85, 95% CI: 1.38–2.89; 60–70 years, HR =3.65, 95% CI: 1.88–7.08; >70 years, HR =7.68, 95% CI: 3.91–15.08] (Table 3). There was no difference in OS for patients based on the treating facility nor racial groups. A mortality benefit was observed in patients with private insurance (HR =0.36, 95% CI: 0.23–0.56). Moreover, advanced tumor stage (T1 vs. T2–4) was associated with worse OS (T2, HR =1.64, 95% CI: 1.14–2.36; T3, HR =3.34, 95% CI: 1.82–6.12; T4a: HR =3.62, 95% CI: 2.38–5.50). Nodal disease and tumor grade were not significant on multivariable analysis (nodal, HR =1.44, 95% CI: 0.80–2.59; grade, HR =2.30, 95% CI: 0.73–7.19). Positive margin status was a negative predictor of OS (HR =1.69, 95% CI: 1.22–2.35). Salivary gland type [minor, major (sublingual, parotid, submandibular)] was not found to be associated with OS. Treatment with RT was associated with improved survival (HR =0.61, 95% CI: 0.39–0.96), whereas chemotherapy (HR =2.83, 95% CI: 1.17–6.85) was associated with worse OS. Log-rank test comparing OS curves indicated a significant benefit (P<0.001) to oncologic clearance at the time of surgery. At the cohort level, OS rates for PAC patients treated surgically at 1-, 5-, and 10-year post-diagnosis were 98.82%, 92.87%, and 80.32%, respectively. DSS data was not available.

Effect of margin status on survival

When evaluating the cohort with positive margins, there was no observed effect of T stage on OS. Kaplan-Meier survival estimates for all patients (Figure 2) did not show an improvement in OS for those treated with surgery and adjuvant RT compared to those treated with surgery alone (P=0.66). Of the 1012 patients (78.33%) with negative margins, 1-, 5-, and 10-year survival rates were 99.09%, 93.31%, and 82.51%, respectively, whereas 280 (21.67%) had positive margins after surgery with 1-, 5-, and 10- year survival rates of 97.84%, 85.42%, and 72.48%, respectively (Figure 3). Though when analyzed independently (Table 4), patients with positive margins undergoing adjuvant RT demonstrate improved OS (HR =0.24, 95% CI: 0.10–0.56), whereas chemotherapy administration (HR =14.84, 95% CI: 3.81–57.86) was associated with decreased OS.

Figure 2 OS by treatment modality. OS, overall survival.

Figure 3 OS by radiation treatment with respect to margin status. OS, overall survival.

Discussion

PAC is a rare disease with an often-indolent course. Surgical resection remains the primary treatment for PAC, but the role of adjuvant RT is debated. A number of studies have published conflicting results on its ability to improve OS (12,16,20). Further, the low prevalence of PAC has made construction of randomized controlled trials (RCTs) difficult, thus, the majority of existing literature is composed of retrospective studies with small sample sizes (21,22). However, certain factors, including high grade, close or positive margins, and lymph node metastasis, have been found to mediate response to RT for patients with PAC (2,12). At present, the ability of RT to improve OS for patients with PAC remains unclear.

Among 1,292 patients, the majority (53.3%) were 50–70 years old at diagnosis, 68.1% female, and 72.0% White (Table 1) (6,8,22). This is in line with other studies noting a female predominance (6,8,22,23). Patel et al. reported a Black-to-White patient ratio of 2.33:1 (6). The racial breakdown of this study differs significantly, but given the lack of available data in the literature it is difficult to determine the reason for this discrepancy.

All patients underwent surgical resection, 238 (19.9%) received adjuvant RT, and 21 (1.6%) received adjuvant chemotherapy. These results coincide with current practice recommendations, which propose resection as the standard of care with approximately 20% needing adjuvant RT (8,11). The low proportion of patients who received chemotherapy is consistent with previous additions to the literature (22). Several studies have found that chemotherapy failed to increase OS in PAC, with some even finding a decrease in OS (21,23). This is likely a result of selection bias, as patients indicated for chemotherapy may have a biologically aggressive variant of adenocarcinoma or metastatic disease that preemptively worsens treatment prognosis. Also, many salivary gland cancer subtypes are not chemosensitive.

Pathologically low-grade tumors were the most common in both surgery (84.7%) and surgery with adjuvant RT (79.6%) groups, though a larger proportion of high-grade tumors underwent adjuvant RT (0.6% vs. 2.2%). Similar trends were observed for tumor stage and nodal status. T1/T2 tumors were commonly treated with surgery alone (85%) compared to the surgery and adjuvant RT group (62.6%), whereas a higher proportion of T3/T4 tumors required adjuvant RT. Overall, advanced grade, stage, and positive nodes were associated with increased likelihood of adjuvant RT, which aligns with the previous literature (8). Despite this, surgery without RT was more common for all groups, with the exception of those with positive nodal disease (Table 1).

Individual patient factors, including age>50 years, advanced tumor stage (T2+), nodal disease (N+), positive margin status, and need for chemotherapy, were all associated with worse OS. In particular, age >70 years was associated with a 20-fold decrease in survival. These relationships have been previously reported (22). However, the effect size of age in this study seems to be uniquely high. Conversely, age <50 years, RT, negative margins, and absence of nodal disease were protective.

Previous studies examining the efficacy of adjuvant RT have reached varying conclusions but generally found no improvement in OS when widely utilized for patients with PAC (6,7,12,13). However, some studies have found survival benefit with adjuvant RT in select high-risk patient groups (advanced disease stage, positive margins) (12,13,16). Our Cox analysis revealed a significant relationship between positive margin status and OS (Table 2). Previous studies have shown margin status as a prognostic factor for patients with salivary gland adenocarcinoma (20,24,25). Most previous investigations of the effect of margin status have focused on the relationship between margin status and OS and recurrence rate (8). However, the factors underlying these observed effects of margin status have remained largely unclear. Margin status and response to adjuvant RT have been the subject of less investigation.

Adjuvant RT had a strong and statistically significant effect on OS for patients with positive surgical margins, reducing the chance of death by up to 76%. This result was interesting, as a recent longitudinal study published in 2021 followed 53 salivary gland adenocarcinoma patients from 1993 to 2011, found no relationship between margin status and response to postoperative RT (22). The implications of this finding are significant, as the role of postoperative RT has been the subject of much debate.

Of note, the results of the unadjusted Kaplan-Meier analysis demonstrated no survival difference between the two groups. However, this finding most likely represents the presence of confounding by indication. Confounding by indication occurs when selection bias for certain treatment modalities results in seemingly unchanged survival outcomes after treatment via basic survival analysis. In this case, a survival advantage may be associated with adjuvant RT, but it is not clear because adjuvant RT is more often utilized for late-stage/high-grade cancer treatment. After adjustment for key prognostic variables in the multivariable Cox model, adjuvant radiotherapy was independently associated with improved survival, suggesting that the unadjusted analysis underestimated its effect.

While our results suggest that adjuvant RT may confer survival benefit for some subsets of patients with PAC, it is important that clinicians also consider the detrimental effects of RT. Radiation to the head and neck region may adversely affect speech, swallowing, and salivary production, cause nausea and fatigue, and often result in thyroid dysfunction (26-28). These side effects can lead to a measurable decline in patient QOL following treatment (26). The results of this study suggest a significant and robust benefit on OS with RT for patients with positive margin status, but indicate unclear benefit in other patient subsets. Should the results of this study be used to guide clinical care, it is important that providers do not indiscriminately subject patients with PAC to RT, as its ability to confer a survival advantage for the larger PAC patient population is not yet supported.

Historically, studies of PAC have included sample sizes of less than 100 due to the rare nature of the disease (21,22). The use of the NCDB allowed for the inclusion of a very large sample of patients and represents a major strength of this study. Further, the multivariable analysis limited the effect of confounding variables, including age, sex, race, tumor stage, margin status, and nodal disease. These features allowed for a comprehensive and representative assessment of the impact of various treatment modalities and the role of clinical features on outcomes for PAC.

The limitations of this study are broadly those that apply to any retrospective database study. While the NCDB includes a robust sample of individuals with PAC, it is incomplete and does not contain all details of a patient’s course. It is a hospital-based registry and not a nationally representative sample. Furthermore, the prolonged data collection period [2004–2020] allows for the introduction of differing treatment standards as a confounding variable. However, there is no reason to believe that surgical techniques or radiation treatment changed in any significant way throughout the time the data was collected. We are also limited by our lack of data on DSS; because the malignancy is rarely fatal, it is likely that most of the deaths during the follow-up period were due to other causes. We attempted to compensate for this by removing patients with significant comorbidities from our analysis. Of note, the limited availability of specific follow-up by patient was unavailable via the NCDB and thus also represents a limitation of this work.

A prospective RCT represents the most valuable future direction of this important topic. Given the rare nature of this disease, this would likely necessitate longitudinal collaboration across several institutions. Such efforts would be of great value, as they would determine any potential causality in the associations outlined here.

Future directions of this work are numerous. Investigation of the effects of radiation dose, fractionation, and timing relative to surgery would allow, though not possible with the dataset utilized for this study, would further the applicability of these results to patients.

Conclusions

We report the findings of a large retrospective database study which aimed to determine the impact of RT on survival for patients with PAC. The results of this study show that RT significantly improves OS in PAC patients with positive margin status, suggesting that adjuvant RT for this subgroup may represent an important consideration for therapeutic paradigms. Further prospective studies are necessary to confirm the causality of our findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1760/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1760/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1760/coif). J.T. serves as an unpaid editorial board member of Translational Cancer Research from May 2025 to April 2027. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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