Molecular characterization of the salivary adenoid cystic carcinoma immune landscape by anatomic subsites.

Adenoid cystic carcinoma (AdCC) is a slow-growing salivary gland malignancy that relapses frequently. AdCCs of the submandibular gland exhibit unique differences in prognosis and treatment response to adjuvant radiotherapy compared to other sites, yet the role of tumor anatomic subsite on gene expression and tumor immune microenvironment (TIME) composition remains unclear. We used 87 samples, including 48 samples (27 AdCC and 21 normal salivary gland tissue samples) from 4 publicly available AdCC RNA sequencing datasets, a validation set of 33 minor gland AdCCs, and 39 samples from an in-house cohort (30 AdCC and 9 normal salivary gland samples). RNA sequencing data were used for single sample gene set enrichment analysis and TIME deconvolution. Quantitative PCR and multiplex immunofluorescence were performed on the in-house cohort. Wilcoxon rank-sum, nonparametric equality-of-medians tests and linear regression models were used to evaluate tumor subsite differences. AdCCs of different anatomic subsites including parotid, submandibular, sublingual, and minor salivary glands differed with respect to expression of several key tumorigenic pathways. Among the three major salivary glands, the reactive oxygen species (ROS)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway signature was significantly underexpressed in AdCC of submandibular compared to parotid and sublingual glands while this association was not observed among normal glands. Additionally, the NRF2 pathway, whose expression was associated with favorable overall survival, was overexpressed in AdCCs of parotid gland compared to minor and submandibular glands. The TIME deconvolution identified differences in CD4+ T cell populations between AdCC of major and minor glands and natural killer (NK) cells among AdCC of minor, submandibular, and parotid glands while plasma cells were enriched in normal submandibular glands compared to other normal gland controls. Our data reveal key molecular differences in AdCC of different anatomic subsites. The ROS and NRF2 pathways are underexpressed in submandibular and minor AdCCs compared to parotid gland AdCCs, and NRF2 pathway expression is associated with favorable overall survival. The CD4+ T, NK, and plasma cell populations also vary by tumor subsites, suggesting that the observed submandibular AdCC tumor-intrinsic pathway differences may be responsible for influencing the TIME composition and survival differences.

Chemoradiotherapy versus radiotherapy in high risk salivary gland cancer.

OBJECTIVE: The aim of this study was to investigate the potential survival benefits associated with chemoradiotherapy (CRT) as opposed to radiotherapy (RT) in patients with resected high-risk salivary gland cancer (SGC), with a specific focus on determining whether these benefits are influenced by the number of high-risk variables. METHODS: Patients who underwent surgical treatment for high-risk SGC were retrospectively enrolled and categorized into either CRT or RT groups. The impact of adjuvant therapy on locoregional control (LRC) and overall survival (OS) was assessed using a multivariable Cox model. RESULTS: A total of 152 patients were included following propensity score-matching. In comparison to RT, CRT did not demonstrate a significant survival advantage in terms of LRC (p = 0.485, HR: 1.14, 95%CI: 0.36-4.22) and OS (p = 0.367, HR: 0.99, 95%CI: 0.17-3.87) in entire population. But among patients with T3/4 stage, high-grade tumors, and 5 or more positive lymph nodes, the addition of chemotherapy to RT significantly (p = 0.042) correlated with a 15% reduction in the risk of cancer recurrence (95%CI: 4-54%). Conversely, in other subgroups with varying combinations of high-risk variables, CRT did not provide additional survival benefits for LRC and OS compared to RT. CONCLUSION: Adjuvant chemotherapy may be considered in conjunction with RT specifically in cases where there is a presence of T3/4 stage, high-grade tumors, and 5 or more metastatic lymph nodes in high-risk SGC.

Letter to editor: Comment on "Clinical disease course and survival outcomes following disease recurrence in adenoid cystic carcinoma with and without NOTCH signaling pathway activation".

The study by Feeney et al. provides critical insights into the prognostic implications of NOTCH pathway activation in adenoid cystic carcinoma (ACC), particularly after disease recurrence. Utilizing both next-generation sequencing and immunohistochemistry, the research delineates the survival outcomes between NOTCH-activated and non-activated ACC groups, highlighting poorer outcomes in the former. The findings advocate for the targeted therapeutic approach and suggest a potential for personalized treatment strategies, emphasizing the need for further research into NOTCH pathway inhibitors and their clinical applications.

PD-L1 and PD-L2 Expression in Different Tumor Stages and Types of Malignant Salivary Gland Neoplasms: A Single-center Experience.

There is a limited amount of data on the role of programmed cell death ligand (PD-L) -1 and PD-L2 in salivary gland carcinomas. We aimed to evaluate the prognostic value of PD-L1 and PD-L2 expressions, which are closely related to immune mechanisms, with respect to salivary gland tumor types and stages. Data from patients with salivary gland masses surgically removed between 2006 and 2021, diagnosed with a malignant salivary gland neoplasm, were retrospectively analyzed. Immunoreactivity for PD-L1 and PD-L2 was performed on resection materials. The mean age of 90 patients was 52.1±18.8 and 46.7% were male. Overall, 55.6% of patients were diagnosed with adenoid cystic carcinoma (ACC), 23.3% with mucoepidermoid carcinoma (MEC), 16.7% with acinic cell carcinoma (AciCC), 3.3% with ductal carcinoma (DC), and 1 patient with pleomorphic adenoma ex carcinoma (PA-ex-CA). In all, 52% of ACC, 12% of AciCC, 24% of MEC, and 12% of DC cases were at stage IV. The tumor diameter, frequencies of lymphovascular invasion, metastasis, positive surgical margin, recurrence, and mortality rates of patients at stages III and IV were significantly larger than those at stages I and II ( P <0.05). The percentages of tumor cell score (TCS) and immune cell score (ICS) for PD-L1 were significantly higher among patients with MEC compared with those with other types of tumors ( P =0.0011). However, the percentages of combined score (CS) for PD-L1 and tumor cell score for PD-L2 were comparable among tumor types ( P >0.05). No significant difference was found in these scores for PD-L1 between tumor stages ( P >0.05), but for PD-L2, all patients at stage I had TCS <1% for PD-L2, while all patients at stages II and III, and 92% of patients at stage IV had TCS ≥1% ( P <0.0001). High expression of PD-L1 was mostly observed in MEC cases ( P =0.0016), while all patients with AciCC had a low PD-L1 expression level ( P =0.0206). The mean tumor diameter, rate of lymphovascular invasion, perineural invasion, metastasis, positive surgical margin, recurrence, type of treatment, mortality, and TILs ratio did not differ significantly according to PD-L1 expression level ( P >0.05). The percentage of tumor-infiltrating lymphocytes was comparable among negative and positive PD-L1 scores according to both 1% and 5% threshold values ( P >0.05). High PD-L1 expression is rare in AciCC, while PD-L1 expression is high in MEC. Our findings underline the importance of future screening for PD-L1 and PD-L2 before patients undergoing immunotherapies in all salivary gland tumors.

Apalutamide and Goserelin for Androgen Receptor-Positive Salivary Gland Carcinoma: A Phase II Nonrandomized Clinical Trial, YATAGARASU.

PURPOSE: To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma. PATIENTS AND METHODS: This trial was an open-label, single-arm, multicenter phase II study. Patients with histologically confirmed unresectable or recurrent/metastatic salivary gland carcinoma with AR expression were included. The primary endpoint was the overall response rate (ORR) according to RECIST v1.1 by an independent central radiology review in the first 24 response-evaluable (RE) patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded. RESULTS: A total of 31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by independent central radiology review was 25.0% [6/24 patients; 95% confidence interval, 9.8%-46.7%; P = 0.11 (one-sided)], which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR positivity ≥70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain. CONCLUSIONS: Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive salivary gland carcinoma and safety consistent with prior experience in prostate cancer.

Oncologic outcomes of the most prevalent major salivary gland cancers: retrospective cohort study from single center.

BACKGROUND: The preoperative diagnosis of salivary gland cancer (SGC) is crucial for the application of appropriate treatment, particularly involving the extension of the resection. METHODS: Retrospective search of medical database identified 116 patients treated surgically with malignant tumors of salivary gland between 2010 and 2020. Analysis included the demographical data, clinical course, type of surgical and adjuvant treatment, histology type and margin status, perivascular invasion (LVI), perineural invasion (PNI), metastatic lymph nodes (LN). Facial nerve function, recurrence-free and overall survival were evaluated. Adequate statistics were used for data analysis. RESULTS: The final cohort included 63 SGC patients, with adenoid cystic carcinoma the most common pathological type (27%, n = 17), followed by adenocarcinoma (17.4% n = 11). T1 and T2 patients accounted for majority cases (n = 46). The lymph node metastases were confirmed with the histopathology in 31.7% (n = 20). Distant metastases were observed in 4.8% of cases (n = 3). 38% (n = 24) of SGC were treated selectively with surgery, 49.2% (n = 31) had postoperative radiotherapy and 15.9% (n = 10)-radio-chemotherapy. The final facial nerve function was impaired in 38% of patients. Mean overall survival (OS) for all patients was 108.7 (± 132.1) months, and was the most favorable for acinar cell carcinoma (118.9 ± 45.4) and the poorest for squamous cell carcinoma (44 ± 32). Cox regression analysis of disease-free survival and OS identified significant association only with patients' age over 65 years, the hazard ratio of 7.955 and 6.486, respectively. CONCLUSIONS: The efficacy of treatment modalities for SGC should be verified with regard to the histopathological type, but also the patients' age should be taken into account.

PON3::LCN1 and HTN3::MSANTD3 Gene Fusions With NR4A3/NR4A2 Expression in Salivary Acinic Cell Carcinoma.

Acinic cell carcinoma of the salivary gland (AciCC) is a low-grade carcinoma characterized by the overexpression of the transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3). AciCC has been the subject of a few molecular research projects. This study delves into AciCC's molecular landscape to identify additional alterations and explore their clinical implications. RNA sequencing and immunohistochemical staining for markers NR4A3/NR4A2, DOG-1, S100, and mammaglobin were utilized on 41 AciCCs and 11 secretory carcinoma (SC) samples. NR4A3 was evident in 35 AciCCs, while the residual 6 were NR4A3-negative and NR4A2-positive; SC samples were consistently NR4A3-negative. A novel fusion, PON3 exon 1- LCN1 exon 5, was detected in 9/41 (21.9%) AciCCs, exhibiting a classical histologic pattern with serous cell components growing in solid sheets alongside the intercalated duct-like component. Clinical follow-up of 39 patients over a median of 59 months revealed diverse prognostic outcomes: 34 patients exhibited no disease evidence, whereas the remaining 5 experienced poorer prognosis, involving local recurrence, lymph node, and distant metastasis, and disease-associated death, 4 of which harbored the PON3::LCN1 fusion. In addition, the HTN3::MSANTD3 fusion was recurrently identified in 7/41 AciCC cases. SC patients lacked both fusions. Immunohistochemistry uncovered differential expression of DOG-1, S100, and mammaglobin across samples, providing nuanced insights into their roles in AciCC. This study accentuates PON3::LCN1 and HTN3::MSANTD3 fusions as recurrent molecular events in AciCC, offering potential diagnostic and prognostic utility and propelling further research into targeted therapeutic strategies.

Incidence, mortality and survival rates of lip, oral cavity and salivary glands cancers in Singapore: A half-century time trend analysis (1968-2017).

OBJECTIVES: To examine trends in incidence and mortality and evaluate overall survival (OS) of oral cancer in Singapore between 1968 and 2017. METHODS: All diagnosed oral cancers by anatomical sites and population size were extracted from the Singapore Cancer Registry and the Department of Statistics Singapore. The trend of age-standardized incidence rate (ASIR) and mortality rate (ASMR) (per 100 000 person-years) of the lip, oral cavity and salivary gland cancers were evaluated by Prais-Winsten regressions for each ethnicity and gender. Kaplan-Meier curves were performed to evaluate the OS by anatomical sites in each age group by ethnicity and sex. RESULTS: Overall, 49, 3494 and 1066 people were diagnosed, and 28, 2310 and 476 died from lip, oral cavity and salivary gland cancers, respectively. The oral cavity cancer ASIR and ASMR reduced from 3.07 (1968-1972) to 2.01(2008-2012) and from 2.06 (1978-1982) to 1.21 (2013-2017) per 100 000 person-years, respectively, with both highest in Indians throughout the whole period. Male:Female ratio ranged from 3.43 (1973-1977) to 1.75 (2013-2017) and from 3.41 (1978-1982) to 2.40 (2013-2017) for ASIR and ASMR, respectively. However, both salivary gland cancer ASIR and ASMR increased from 0.50 (1968-1972) to 0.80 (2008-2012) and from 0.18 (1968-1982) to 0.42 (1988-1992) per 100 000 person-years, respectively, with both higher in males since 1993. Oral cavity cancer ASIR decreased for males aged ≥60, and Indian females ≥25, but increased among Chinese females aged ≥60. Oral cavity cancer ASMR decreased among Chinese aged 25-59, and among Malay males and Indian females. Salivary gland cancer ASIR increased among Chinese males aged ≥60 and Malay males aged 25-59; while ASMR increased among Chinese males aged ≥60. The median OS for oral cavity, lip and salivary gland cancers were 3.0, 9.3 and 18.1 years, respectively, with females surviving longer than males. CONCLUSIONS: Singapore has experienced a decline in the incidence and mortality of lip, oral cancer, an increase in in the incidence and mortality of salivary gland cancer, with an increase in the median overall survival rate. Monitoring the magnitude of oral cancer burden and the demographic, and temporal variations is necessary for tailoring health planning and setting priorities for future clinical care and research.

Salivary gland adenoid cystic carcinoma in the U.S population: Importance of grade, site of metastases, and adjuvant radiation for survival.

BACKGROUND: Adenoid cystic carcinoma (AdCC) is a rare and relatively heterogenous salivary gland malignancy, for which there is debate regarding grading, and clinical prognostic factors, including the role of adjuvant radiotherapy. METHODS: Surveillance, Epidemiology, and End Results (SEER) data were reviewed for AdCC cases from 2000 to 2018. RESULTS: A total of 1978 patients with AdCC were identified. Most patients were between 50 and 59 years of age (21.4 %), female (59.9 %), and Caucasian (76.8 %). Most tumors were localized at presentation (44.3 %), and moderately differentiated (or grade II) (43.7 %). Overall and DSS 5-year survival rates were 70.7 % (95 % CI, 69.9-78.8), and 78.6 % (95 % CI, 77.6-79.6). The best overall 5-year survival rate was observed for those treated with surgery plus radiation, 76.8 % (95 % CI, 75.5-78.1). Multivariate analysis revealed male sex, age > 65 (H.R. 2.659 (95 % CI,2.291-3.098), p < .001), grade III/IV (H.R.5.172 (95 % CI, 3.418-7.824), p < .001), nodal metastasis, distant metastasis (H.R. 2.400 (95 % CI, 2.178-2.645), p < .001), chemotherapy only, and combination therapy as negative prognostic factors, and receiving surgery plus radiation therapy (H.R.0.586 (95 % CI, 0.505-0.679), p < .001) as a positive prognostic factor. When limited just to the lungs, had much better survival than those patients with distant metastases to other sites such as the bones and liver (p < .001). CONCLUSION: This SEER study identifies grade, particularly III and IV, to be the strongest single predictor of worse survival. Patients did best when treated with surgery and postoperative radiotherapy. These results can inform future management of patients with this challenging cancer type.

Surgical Resection Improves Overall Survival in cT4b Major Salivary Gland Cancer.

OBJECTIVE: To compare surgical and nonsurgical definitive treatment in cT4b major salivary gland cancer (MSGC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2004 to 2019 National Cancer Database. METHODS: The NCDB was queried for patients with cT4b MSGC (N = 976). Patients undergoing definitive treatment with (1) surgical resection + adjuvant therapy, (2) radiotherapy (RT) alone, or (3) chemoradiotherapy (CRT) were included in Kaplan-Meier and Cox survival analyses. RESULTS: Of 219 patients undergoing definitive treatment, 148 (67.6%) underwent surgical resection + adjuvant therapy and 71 (32.4%) underwent RT or CRT. There were no documented mortalities within 90 days of surgical resection. Tumor diameter and nodal metastasis were associated with decreased odds of undergoing definitive treatment (P < 0.025). Patients with positive surgical margins (PSM) had higher 5-year overall survival (OS) than those undergoing definitive RT or CRT (48.5% vs 30.1%, P = 0.018) and similar 5-year OS as those with negative margins (48.5% vs 54.0%, P = 0.205). Surgical resection + adjuvant therapy (adjusted hazard ratio: 0.55, 95% confidence interval [CI]: 0.37-0.84) was associated with higher OS than definitive RT or CRT (P < 0.025). A separate cohort of 961 patients with cT4a tumors undergoing surgical resection + adjuvant therapy was created; cT4a and cT4b (hazard ratio: 1.02, 95% CI: 0.80-1.29, P = 0.896) tumors had similar OS. CONCLUSION: A minority of patients with cT4b MSGC undergo definitive treatment. Surgical resection + adjuvant therapy was safe and associated with higher OS than definitive RT or CRT, despite high rate of PSM. In the absence of clinical trial data, appropriately selected patients with cT4b MSGC may benefit from surgical resection.

Patterns and Trends in Adjuvant Therapy for Major Salivary Gland Cancer.

OBJECTIVE: To investigate adjuvant therapy indications, utilization, and associated survival disparities in major salivary gland cancer (MSGC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2006 to 2017 National Cancer Database. METHODS: Patients with surgically resected MSGC were included (N = 11,398). pT3-4 classification, pN2-3 classification, lymphovascular invasion, pathologic extranodal extension (pENE), and positive surgical margin (PSM) were considered indications for adjuvant radiotherapy (aRT). pENE and PSM were considered possible indications for adjuvant chemotherapy. Multivariable logistic and Cox regression models were implemented. RESULTS: Among 6694 patients with ≥ $\ge $ 1 indication for aRT, 1906 (28.5%) received no further treatment and missed aRT. Age, race, comorbidity status, facility type, and distance to reporting facility were associated with missed aRT (P < .025). Among 4003 patients with ≥1 possible indication for adjuvant chemoradiotherapy (aCRT), 914 (22.8%) received aCRT. Patients with pENE only (38.5%) and both pENE and PSM (44.0%) received aCRT more frequently than those with PSM only (17.0%) (P < .001). Academic facility was associated with aCRT utilization (P < .05). aCRT utilization increased between 2006 and 2017 in both academic (14.8% vs 23.9%) and nonacademic (8.8% vs 13.5%) facilities (P < .05). Among 2691 patients with ≥1 indication for aRT alone, missed aRT portended poorer OS (hazard ratio [HR]: 1.61, 95% confidence interval [CI]: 1.28-2.03, P < .001). Among 4003 patients with ≥1 possible indication for aCRT, aRT alone (HR: 1.02, 95% CI: 0.89-1.18, P = .780) and aCRT were associated with similar OS. CONCLUSION: Missed aRT in MSGC occurs frequently and portends poorer OS. Further studies clarifying indications for aCRT are required.

Prognosis of primary breast salivary gland-type carcinoma: a propensity score-matching analysis with invasive carcinoma of no special type based on the SEER database for years 2010-2020.

BACKGROUND: Primary breast salivary gland-type carcinoma has weak evidence to support its management due to its rare occurrence and limited data regarding its clinicopathological features and prognosis. Therefore, this study aimed to assess clinicopathological features and prognosis for this type of carcinoma diagnosed over the past decade and compared those to the common breast invasive carcinoma of no special type (NST). METHODS: This study used the Surveillance, Epidemiology, and End Results (SEER) database to extract data regarding primary breast salivary gland-type carcinoma. Using a propensity score-matching approach, the prognosis was compared with invasive carcinoma, NST. RESULTS: This study included 488 cases of salivary gland-type carcinoma and 375,660 cases of invasive carcinoma, NST, giving an occurrence ratio of 1 to 770. Adenoid cystic carcinoma (81%) formed the majority of salivary gland-type carcinoma, followed by secretory carcinoma (13%). For salivary gland-type carcinoma, acinic cell carcinoma histological type, tumor grade 3, HER2-overexpressed status, and higher AJCC stage groups were significant worse prognostic factors for breast cancer-specific survival in univariate analyses (p < 0.05). Nonetheless, tumor grade 3 and higher AJCC stage groups remained as significant independent prognostic factors in multivariate analysis (p < 0.05). The apparent better breast cancer-specific survival of salivary gland-type carcinoma as compared to that of invasive carcinoma, NST, was diminished following adjustment for differences in baseline clinicopathological features and treatment-related variables. CONCLUSIONS: This study suggests that when managing primary breast salivary gland-type carcinoma, greater emphasis should be given to the tumor grade and AJCC stage group in addition to acinic cell carcinoma histological type and HER2 overexpression. Conventional prognostic factors are important as salivary gland-type carcinoma had similar prognosis as invasive carcinoma, NST, following adjustment for confounding variables.

Choice of Adjuvant Radiotherapy Facility in Major Salivary Gland Cancer.

OBJECTIVE: Undergoing surgery and adjuvant radiotherapy (aRT) at the same facility has been associated with higher overall survival (OS) in head and neck squamous cell carcinoma. Our study investigates whether undergoing surgery and aRT at the same academic facility is associated with higher OS in major salivary gland cancer (MSGC). METHODS: The 2006-2018 National Cancer Database was queried for patients with MSGC undergoing surgery at an academic facility and then aRT. Multivariable binary logistic and Cox proportional hazards regression models were implemented. RESULTS: Of 2801 patients satisfying inclusion criteria, 2130 (76.0%) underwent surgery and aRT at the same academic facility. Residence in a less populated area (adjusted odds ratio [aOR] 1.69, 95% confidence interval [CI] 1.16-2.45), treatment without adjuvant chemotherapy (aOR 1.97, 95% CI 1.41-2.76), and aRT duration (aOR 1.02, 95% CI 1.01-1.04) were associated with undergoing surgery and aRT at different facilities on multivariable logistic regression adjusting for patient demographics, clinicopathologic features, and adjuvant therapy (p < 0.01). Five-year OS was higher in patients undergoing surgery and aRT at the same academic facility (68.8% vs. 61.9%, p < 0.001). Undergoing surgery and aRT at different facilities remained associated with worse OS on multivariable Cox regression (aHR 1.41, 95% CI 1.10-1.81, p = 0.007). CONCLUSION: Undergoing surgery and aRT at the same academic facility is associated with higher OS in MSGC. Although undergoing surgery and aRT at the same academic facility is impractical for all patients, academic physicians should consider same-facility treatment for complex patients who would most benefit from clear multidisciplinary communication. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3620-3632, 2024.

Molecular Profiling and the Impact of Treatment on Outcomes in Adenoid Cystic Carcinoma Type I and II.

PURPOSE: Adenoid cystic carcinoma (ACC) is an uncommon salivary gland cancer with no approved therapies available to treat advanced, incurable disease. Recent molecular profiling efforts have identified two important subtypes: the more aggressive ACC-I is characterized by Notch pathway alterations and MYC amplification whereas ACC-II demonstrates a more indolent phenotype and TP63 overexpression. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved de-identified samples from 438 patients with ACC with tumor samples sent for commercially-available molecular profiling (Caris Life Sciences). Next-generation whole-exome and whole-transcriptomic sequencing was performed on primary and metastatic samples. Immunostaining for PD-L1 and RNA deconvolution (quanTIseq) was used to explore the tumor immune microenvironment (TME). Real-world clinical and survival outcome metrics were extracted from insurance claims data. RESULTS: MYC expression was 1.61-fold higher (39.8 vs. 24.7; P < 0.0001) among NOTCH1-mutant ACC-I tumors, whereas MYB/L1 fusion rates were similar among ACC-I/II. The median B-cell fraction in the TME was higher among ACC-II (7.1% vs. 5.8%; P < 0.01), although infiltrating T cells subsets were low among either ACC subgroup (both <1%). When pooling systemic treatment categories, ACC-I patients had worse outcomes with available therapies (HR, 3.06; 95% confidence interval, 1.65-5.68; P < 0.01), with no significant difference in overall survival between ACC-I/II based on chemotherapy or VEGFR tyrosine kinase inhibitor exposure in smaller subsets. CONCLUSIONS: We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and -II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.

Evaluation of the efficacy of adjuvant radiotherapy versus chemoradiotherapy in patients with salivary gland tumors.

AIMS: The aim of this study was to compare the efficacy of adjuvant radiotherapy (RT) versus adjuvant chemoradiotherapy (CRT) in patients with salivary gland tumors (SGTs). MATERIALS AND METHODS: Data from patients who underwent adjuvant RT for a diagnosis of SG cancer at Ankara Atatürk Education and Research Hospital, Ankara Numune Education and Research Hospital and Ankara Bilkent City Hospital between September 01, 2009 and September 01, 2022 were analysed retrospectively. We evaluated the efficacy of RT alone versus CRT in these patients in terms of acute response, treatment tolerance, overall survival (OS), and disease-free survival (DFS). RESULTS: Fifty-five patients who underwent RT between September 14, 2009 and August 04, 2022 at Ankara Atatürk Education and Research Hospital, Ankara Numune Education and Research Hospital and Ankara Bilkent City Hospital were included in this study. Eight patients who did not meet the study criteria were excluded; thus, the analysis was performed for 47 patients. The median follow-up period was 60 months (range: 6-160 months). The median patient age was 53 years (range: 18-86 years). Thirty-nine patients (83%) had parotid tumors and eight patients (17%) had submandibular cancer. The time from surgery to RT was 48 days (range: 20-126 days). Intensity-modulated radiotherapy was administered to all patients and the median RT dose was 66 Gy (range: 52-70 Gy). Concomitant chemotherapy (CCT) (40 mg/m 2 of cisplatin weekly) was administered to 13 patients (27.7%). Acute adverse events were observed in 17 patients (36.2%). Interruption of RT was noted for only six patients (12.8%), and this proportion did not differ significantly between the CRT and RT-only arms ( P = 0.538). Acute side effects were observed in 17 patients (36.2%), and there were no significant relationships between acute side effects and the administration of CCT ( P = 0.112). Recurrence was observed in 10 patients (21.3%). All recurrences were locoregional and no distant metastases were observed during the follow-up period. The median DFS of the patients was 48 months (range: 4-160 months), 1-year DFS was 86%, 2-year DFS was 83.5%, and 5-year DFS was 77.9%. There was no statistically significant difference in DFS between the adjuvant CRT and RT-alone arms ( P = 0.114). At the date of last follow-up, 14 patients (29.8%) had died. The median OS of the patients was 58.5 months (range: 6-160 months), 1-year OS was 91.4%, 2-year OS was 86.8%, and 5-year OS was 78%. There was no statistically significant difference in OS between the adjuvant CRT and RT-only arms ( P = 0.453). CONCLUSION: Stage was identified as the most important prognostic factor for DFS and OS. No significant differences in OS, DFS, or acute side effects were observed between the CRT and RT-only arms. Additional studies are needed to identify the subgroup of SGT patients for which CRT is most warranted.

Lung cancer metastasizing to salivary glands: Systematic review.

ABSTRACTS: Metastasis to salivary glands from the secondary source outside the head and neck region is extremely rare and Carcinoma Lung is one of the rarest sources of distant spread to salivary glands. Owing to missed diagnosis and misdiagnosis, accurate identification of clinical and pathological aspects of these metastatic lesions remains a challenging task. Many studies regarding metastasis to the oral cavity have been already documented in the literature, but very little research work has been done to analyse the cases of lung cancer metastasis as the sole primary source, particularly to salivary glands. Thus this review was conducted to analyse the published cases of lung cancer metastasizing to salivary glands as the only primary source till date. An electronic search of the published literature was performed without publication year limitation in PubMed/ Medline, Scopus, Google Scholar, Web of Science, Science direct, Embase, and Research gate databases, using Mesh keywords like (Lung cancer', OR 'Lung carcinoma), AND (Metastasis OR Metastases), And (Salivary glands OR Parotid gland OR Submandibular gland OR Sublingual gland). We also searched all related journals manually. The reference list of all articles was also checked. Our research revealed 34 relevant papers between 1965-2022 with a total of 44 patients. The most prevalent diagnosed metastatic Lung cancer was Small cell lung cancer. Parotid was the most common gland involved in metastasis. 48% of patients died of metastasis with a mean survival time of 2.2 years. Salivary gland metastasis from Lung cancer is very rare and has a poor prognosis. More cases need to be published in order to raise awareness of these lesions and gain a better understanding of their characteristics.

Outcome of Ordinary Polymorphous Adenocarcinomas of the Salivary Glands in Comparison With Papillary and Cribriform Subtypes.

BACKGROUND/AIM: Polymorphous adenocarcinoma (PAC) is a low-grade salivary gland malignancy in contrast to variants with papillary (PAP) or cribriform (CASG) architecture and confers the second most common malignancy of minor salivary glands. Our study aimed to identify prognostic factors and to evaluate histomorphological and molecular diagnostic criteria of PACs. PATIENTS AND METHODS: A series of 155 PACs, including 10 PAPs and 12 CASGs from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW) and the Hamburg Salivary Gland Reference Centre (HRC) were analyzed. RESULTS: One fifth of the tumors were located in the major salivary glands and PACS/CASGS invariably lacked p40 expression. Fifty-two percent of PACs showed a PRKD1 E710D mutation. Ordinary PACs had a disease-specific 10-year survival probability of 97% compared to 90% when combining PAPs and CASGs. T-stage at diagnosis was a prognostic factor with 98% for stages T1/T2 versus 75% for T3/T4. CONCLUSION: Diagnostic algorithms for the PAC/CASG spectrum of tumors need to be improved and should include molecular markers.

Treatment Efficacy of PD-1 Inhibitor Therapy in Patients With Recurrent and/or Metastatic Salivary Gland Carcinoma.

BACKGROUND/AIM: The efficacy of programmed cell death 1 (PD-1) inhibitor therapy for patients with recurrent and/or metastatic salivary gland carcinoma (R/M SGC) remains unclear. PATIENTS AND METHODS: We retrospectively analyzed 36 patients with R/M SGC treated with PD-1 inhibitor. The expression of programmed cell death ligand 1 (PD-L1) and mismatch repair (MMR) proteins was also analyzed. RESULTS: The objective response rate (ORR) was 11.1%. The histopathological subtypes of patients who achieved complete response or partial response were salivary duct carcinoma (SDC) in three patients and poorly differentiated carcinoma in one patient, all of whom showed a positive PD-L1 expression. The expression of MMR proteins was not associated with the efficacy of PD-1 inhibitors. CONCLUSION: Although the efficacy of PD-1 inhibitor therapy in R/M SGC is limited, certain patients may respond and achieve long-term disease control. There is a potential therapeutic effect in SDC patients with positive PD-L1 expression.

Prognostic factors and overall survival in a 15-year followup of patients with malignant salivary gland tumors: a retrospective analysis of 193 patients.

INTRODUCTION: Malignant tumors of the salivary glands are uncommon pathological entities, representing less than 5% of head and neck neoplasms. The prognosis of patients with malignant tumors of the salivary glands is highly variable and certain clinical factors can significantly influence overall survival. OBJECTIVE: To analyze the clinicopathologic and sociodemographic characteristics that influence survival in patients with malignant tumors of the salivary glands METHODS: This retrospective study analyzed sex, age, race, education level, tumor location, tumor size, lymph node involvement, distant metastasis, margin status, treatment type, marital status, method of health care access and 15-year overall survival in 193 patients with malignant tumors of the salivary glands. The X², log-rank Mantel-Cox, multinomial regression and Cox logistic regression tests were used (SPSS 20.0,p < 0.05). RESULTS: The most common histological types were adenocarcinoma (32.1%), adenoid cystic carcinoma (31.1%) and mucoepidermoid carcinoma (18.7%). The 15-year overall survival rate was 67.4%, with a mean of 116±6 months. The univariate analysis revealed that male sex (p = 0.026), age > 50 years (p=0.001), referral origin from the public health system (p=0.011), T stage (p= 0.007), M stage (p< 0.001), clinical stage (p< 0.001), compromised surgical margins (p= 0.013), and chemotherapy (p< 0.001) were associated with a poor prognosis. Multivariate analyses also showed that age > 50 years was independently associated with a poor prognosis (p= 0.016). The level of education was the only factor more prevalent in older patients (p= 0.011). CONCLUSION: Patients with malignant tumors of the salivary glands older than 50 years have a worse prognosis and an independent association with a low education level.

Lymph node ratio as a predictor for minor salivary gland cancer in head and neck.

BACKGROUND: We investigate whether pathological continuous variables of lymph nodes were related with survival results of carcinomas of minor salivary gland carcinoma in head and neck. METHODS: Forty-four cases with minor salivary gland carcinoma who underwent both primary resection and neck dissection were retrospectively enrolled. The pathological continuous variables were evaluated by the number of positive lymph nodes, lymph node ratio, and log odds of positive lymph nodes. Receiver operating curve analysis was used for the cut-off values of the carcinoma-specific death. Log-rank test and Cox's proportional hazards model were used for uni-/multi-variate survival analyses adjusting for pathological stage, respectively. RESULTS: Lymph node ratio = 0.05 as well as log odds of positive lymph nodes = - 2.73 predicted the carcinoma-specific death. Both lymph node ratio and log odds of positive lymph nodes were significantly related with survival outcomes by the univariate analysis. Lymph node ratio ≥ 0.05 was associated with shorter disease-specific (hazard ratio = 7.90, 95% confidence interval = 1.54-57.1), disease-free (hazard ratio = 4.15, 95% confidence interval = 1.48-11.2) and overall (hazard ratio = 4.84, 95% confidence interval = 1.05-24.8) survival in the multivariate analysis. CONCLUSION: A higher lymph node ratio of minor salivary gland carcinoma is a predictor of shorter survival results.