Although immune checkpoint inhibitors (ICIs) are effective in some patients with salivary gland carcinoma (SGC), biomarkers which predict the efficacy and prognosis of SGC patients treated with pembrolizumab have not been identified. We conducted a multi-institutional retrospective cohort study to evaluate the efficacy and safety of pembrolizumab monotherapy in patients with recurrent and/or metastatic SGC and to determine optimal cut-off values of the combined positive score (CPS) and tumor proportion score (TPS) as numerical expression levels of programmed death-ligand 1 (PD-L1), which predict the efficacy of pembrolizumab. Furthermore, we investigated the association of patient characteristics and hematological markers with clinical outcomes, including overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). From 2016 to 2021, 27 patients were included in the analysis. ORR of SGC was 25.9%. Optimal cut-off values of CPS and TPS were 15 and 25%, respectively. ORRs of CPS-high and TPS-high were 55.6 and 75.0%, respectively, and significantly higher than those of CPS-low and TPS-low. Furthermore, patients with a low platelet-lymphocyte ratio (PLR) had a significantly longer PFS. No grade 4 or greater adverse events were observed. This study demonstrated the efficacy and safety of pembrolizumab monotherapy and identified optimal cut-off values of CPS and TPS.

UNASSIGNED: Radiotherapy following primary operation is strongly recommended for salivary gland carcinomas (SGCs) with adverse features. The interval between surgery and the initiation of radiotherapy (SRT) varied and a prolonged SRT may cause failure of cancer treatment. However, the association of SRT with survival is unclear in major SGCs.
UNASSIGNED: This retrospective study included a total of 346 patients who underwent radiotherapy after the primary operation from Fudan University Shanghai Cancer Center from 2005 to 2020. The best cutoff value of the SRT was determined by the maximum log-rank statistic method. The primary endpoint of the study was overall survival (OS). Correlations between variables and OS were conducted by the univariable analysis using the Log-rank method, and a multivariate Cox proportional hazards regression was performed to identify the independent prognostic factors associated with OS. The estimated survival rates were captured using the Kaplan-Meier method.
UNASSIGNED: With a median follow-up time of 70.31 months, the estimated 5-year OS, LRFS, and DMFS were 83.3%, 80.1%, and 75.9%, respectively. The cutoff value for SRT was 8.5 weeks, while age, T stage, N stage, perineural invasion (PNI), pathological aggression, chemotherapy, and SRT were associated with OS in the univariable analysis. The Cox regression analysis demonstrated that older age (P < 0.001), T3-4 tumors (P = 0.007), positive N stage (P < 0.001), pathological aggression (P = 0.014), and longer SRT (P = 0.009) were independent prognostic factors for major SGCs. Using the stratification model, we observed that delay in the SRT was associated with worse OS (P = 0.006) in the high-risk group, whereas no significant difference was observed in the low-risk subgroup (P = 0.61).
UNASSIGNED: The delay in the initiation of postoperative radiotherapy may be a prognostic factor for patients with major SGCs. It was suggested that radiotherapy should be delivered within 8.5 weeks following the operation, especially for patients with ≥2 risk factors, including older age, high pathological aggression, T3-4 tumors, and positive N stage.

UNASSIGNED: Low-grade salivary gland carcinoma is regularly treated with surgical therapy of the salivary gland without elective neck dissection in T1/2 carcinomas, either alone or with adjuvant radiation therapy. However, occult metastasis and locoregional recurrence influence therapy and outcome. Tumor budding is an emerging prognostic pathological factor in many carcinomas, but has not yet been adequately considered in salivary gland carcinomas.
UNASSIGNED: We conducted a retrospective single-center study of 64 patients diagnosed with low-grade carcinoma of the major salivary glands treated between 2003 and 2017. Pathological risk factors and TNM classification were thoroughly assessed for each case. All hematoxylin and eosin (HE)-stained histological specimens underwent careful examination, and tumor budding was identified following the guidelines set forth by the International Tumor Budding Consensus Conference in 2016.
UNASSIGNED: Tumor budding was not statistically significant concerning 5-year survival rate (5-YSR) (p=0.969) and mean overall survival (log-rank p=0.315). Whereas 5-year disease-free survival rate (5-YDFSR) was 87% in the low tumor budding group and 61.1% in the intermediate and high tumor budding group (p=0.021). Mean disease-free survival accounted for 100.2 months (CI: 88.6;111.9) in the low budding score group and 58.7 months (CI: 42.8;74.6) in the other group (log-rank p=0.032). Notably, pT1/2 showed significantly lower tumor buds than pT3/4 stages (2.43 tumor buds/0.785 mm2 vs. 4.19 tumor buds/0.785 mm2, p=0.034). Similar findings were noted comparing nodal-positive and nodal-negative patients, as well as patients with and without lymphovascular invasion and perineural invasion (each p<0.05).
UNASSIGNED: Tumor budding might be used as an additional prognostic factor for recurrence in low-grade salivary gland carcinoma, seemingly associated with a higher nodal metastasis rate and advanced tumor stages and a worse 5-YDFSR. Consequently, the evaluation of tumor budding in resection specimens of low-grade salivary gland tumor may prove valuable in decision-making for neck dissection and follow-up strategy.

Epithelial-myoepithelial carcinoma (EMC) is a rare tumor, characterized by two different cell populations and both demonstrate a malignant nature microscopically. It constitutes less than 2% of all salivary gland malignancies. The World Health Organization (WHO) has classified this disease as a separate pathological category. The diagnosis of this tumor is arrived by biopsy. It shows slow growth and is small in size; it appears in ulcerative form of mucosa in some cases. Gland cells consist of two layers of outer myoepithelium cells and inner epithelial cells. Vimentin staining is positive. It shows calponin, muscle-specific actin, S100, smooth muscle actin, p63, and smooth muscle myosin heavy chain I. Examining different sets of data reveals that tumors exhibiting a solid growth pattern, nuclear atypia, DNA aneuploidy, and increased proliferative activity typically display a more aggressive nature, accompanied by a heightened likelihood of local recurrences and metastases. The clinical and radiological observations frequently resemble those of a benign tumor. Due to the uncommon nature of EMC, there is currently no established standard treatment protocol. It is considered a low-grade tumor where good resection holds better results. Individuals displaying histopathological indicators of aggressive disease should be evaluated for potential adjuvant radiotherapy. We present a case of a patient who had recurrence twice in a period of seven years despite surgical management, chemotherapy, and radiotherapy.

Primary squamous cell carcinoma of the parotid gland (pSCCP) has long been recognized as a separate entity and is included in the WHO classifications of salivary gland tumors. However, it is widely accepted among head and neck pathologists that pSCCP is exceptionally rare. Yet, there are many publications describing series of pSCCP and data from SEER and other cancer register databases indicate erroneously an increasing incidence of pSCCP. Importantly, pSCCP and metastatic (secondary) squamous cell carcinoma to the parotid gland (mSCCP) have nearly identical histological features, and the diagnosis of pSCCP should only be made after the exclusion of mSCCP. Moreover, all of the histological diagnostic criteria proposed to be in favor of pSCCP (such as, for example, dysplasia of ductal epithelium) can be encountered in unequivocal mSCCP, thereby representing secondary growth along preexistent ducts. Squamous cell differentiation has also been reported in rare genetically defined primary parotid carcinomas, either as unequivocal histological squamous features (e.g., NUT carcinoma, mucoepidermoid carcinoma), by immunohistochemistry (e.g., in NUT carcinoma, adamantinoma-like Ewing sarcoma, basal-type salivary duct carcinoma, mucoepidermoid carcinoma), or a combination of both. Another major issue in this context is that the International Classification of Diseases (ICD) coding system does not distinguish between primary or metastatic disease, resulting in a large number of patients with mSCCP being misclassified as pSCCP. Immunohistochemistry and new molecular biomarkers have significantly improved the accuracy of the diagnosis of many salivary gland neoplasms, but until recently there were no biomarkers that can accurately distinguish between mSCCP and pSCCP. However, recent genomic profiling studies have unequivocally demonstrated that almost all SCCP analyzed to date have an ultraviolet light (UV)-induced mutational signature typical of mSCCP of skin origin. Thus, mutational signature analysis can be a very useful tool in determining the cutaneous origin of these tumors. Additional molecular studies may shed new light on this old diagnostic and clinical problem. This review presents a critical view of head and neck experts on this topic.

OBJECTIVE: The incidence of salivary duct carcinoma (SDC) seems to be underestimated due to inaccurate classification. Further, the frequency of SDC patients with targeted therapy options according to current guidelines is unclear. Therefore, this study aimed at (a) describing the proportion of SDC among salivary gland carcinoma (SGC) before and after reclassification of cases initially classified as adenocarcinoma, not otherwise specified (ANOS); and (b) quantifying the frequency of SDC patients with targeted therapy options.
METHODS: All patients with SDC or ANOS treated in a tertiary care center between 1996 and 2023 were identified. Histopathological diagnosis was verified for patients primarily diagnosed with SDC and reviewed for patients initially diagnosed with ANOS. Clinical data for SDC patients were retrieved from clinical charts. Immunohistochemical (IHC) androgen receptor (AR) and HER2 staining was performed.
RESULTS: Among 46 SDC, 34 were primarily diagnosed as SDC and 12 had initially been classified as ANOS. The proportion of SDC among SGC was 12.1% and was rising when comparing the time periods 2000-2015 (7.1-11.5%) versus 2016-2023 (15.4-18.1%). Nuclear AR staining in > 70% of tumor cells was found in 56.8% and HER2 positivity (IHC 3 +) in 36.4% of cases. 70.5% of patients showed AR staining in > 70% of tumor cells and/or HER2 positivity and therefore at least one molecular target. 5-year overall and disease-free survival (DFS) were 62.8% and 41.0%. Multivariate Cox regression revealed positive resection margins (HR = 4.0, p = 0.03) as independent negative predictor for DFS.
CONCLUSIONS: The results suggest a rising SDC incidence and show that the extent of the AR and HER2 expression allows for targeted therapy in most SDC cases.

Lymphoepithelial carcinoma (LEC) of the salivary gland is a rare squamous cell carcinoma. LEC commonly presents in the parotid and submandibular glands and rarely in the sublingual gland. While salivary gland LEC has a predilection for Inuit-Yupik and Chinese populations, few cases have been reported in the Hispanic population and none for sublingual glands in the English language literature. Here, we present the seventh case report in the English language literature for sublingual LEC and the first case observed in a Hispanic patient.

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OBJECTIVE: This study aims to analyze the behavior and treatment of adenoid cystic carcinoma (AdCC) in the pediatric and young adult population and to identify factors affecting overall survival (OS).
METHODS: The study analyzed salivary gland malignancies in patients aged 0-21 with AdCC histology using the National Cancer Database from 2004 to 2018.
RESULTS: A total of 72 patients (59.7% parotid, 36.1% submandibular, 1.4% sublingual, 2.8% unspecified) met criteria. Median age was 18 years [range: 0-21]. High-grade dysplasia was present in 67% of cases. Therapy consisted of primary surgery for all cases, regional lymph node dissection (LND) (74%), radiotherapy (71%), chemotherapy (8%), and chemoradiation (7%). The 5-year OS rate was 93.2% [95% confidence interval (CI): 86.9%-99.9%], respectively. Patients who underwent associated LND had improved OS (p = .0083, log-rank test) with a 5-year OS at 82.4% [95% CI: 66.1%-100%] versus 97.6% [95% CI: 93.0%-100%]. A significant difference in OS was found with unfavorable outcomes after positive marginal status: 5-year OS 84.1% [95% CI: 71.0%-99.7%] versus 100% [95% CI: 100%]; p < .001. Adjuvant therapy did not seem to impact the outcome.
CONCLUSIONS: This study confirms that AdCC in children and young adults has an overall good prognosis despite frequent high grade. It suggests that cervical LND may be of importance, but the value of systematic adjuvant therapy is not confirmed. These findings emphasize the importance and relevance of population-based studies in shaping clinical practice and informing the design of future prospective investigations.

BACKGROUND: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis.
METHODS: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety.
RESULTS: This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-‍34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-‍81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1).
CONCLUSIONS: The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC.
BACKGROUND: FIH study, NCT02564900; DDI study, NCT03383692.