Brain metastases in patients with salivary duct carcinoma: A retrospective study.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade adenocarcinoma with a 5-year survival rate of 40%. Although drug therapy has improved patients' prognosis, the impact of brain metastasis (BM) remains poorly understood. We aimed to retrospectively examine the incidence of BM in patients with SDC (n = 464) and develop a tool to estimate their prognoses. METHODS: We retrospectively examined 464 patients with SDC enrolled in a multicenter study. We investigated the incidence of BM, overall survival (OS) rates, and factors affecting prognosis in patients with BM. We also developed an SDC-graded prognostic assessment (GPA) score for disease prognostication. RESULTS: Sixty-five (14%) patients had BM. The median OS (mOS) was 13.1 months. On univariate and multivariate analyses, factors such as Eastern Cooperative Oncology Group Performance Status >1, human epidermal growth factor receptor 2-negative status, and locoregional uncontrolled disease were associated with poor OS. SDC-GPA scores according to the prognostic factors were 0, 1, 2, and 3 points, and mOS estimates were 50.5, 16.1, 3.9, and 1.2 months, respectively (p < 0.001). CONCLUSION: The SDC-GPA score emerged as a useful prognostication tool for patients with BM.

Differential expression of TRKB tyrosine kinase in the two histological types of parotid salivary duct carcinoma with cancer aggressiveness.

Parotid salivary duct carcinoma (SDC) is a rare and aggressive parotid gland carcinoma (PGC). SDC has two origins: de novo and ex pleomorphic adenoma (SDC ex PA); however, because of its rarity, the clinical and molecular features of the two types of SDC are not sufficiently understood. Here, we studied the differences in their clinicopathological and molecular features using clinical specimens while comparing them to those of adenoid cystic carcinoma (AdCC), an intermediate-grade PGC. Clinicopathological analysis of tissues from patients with PGC revealed significant associations between histological types and malignant phenotypes, including nodal metastasis, recurrence, vascular invasion, and neural invasion, and revealed more malignant phenotypes of de novo SDC than of SDC ex PA. The de novo SDC showed a significantly higher frequency of intra-neural invasion (intra-NI) and vascular invasion than AdCC and SDC ex PA. PGCs with high intra-NI were significantly correlated with malignant phenotypes and survival rates. Recently, we observed the overexpression of tropomyosin receptor kinase B (TRKB), a receptor tyrosine kinase, in PGC cells. Here, immunohistochemical and clinicopathological analyses showed that TRKB was highly expressed in SDC cells, particularly de novo SDC cells, and was significantly associated with poor survival and highly malignant phenotypes, including intra-NI and vascular invasion. Collectively, these data show that TRKB expression is significantly elevated in PGC, particularly in de novo SDC, and can be one of the biomarkers of their aggressiveness.

Gastric Metastasis from Salivary Duct Carcinoma Mimicking Scirrhous Gastric Cancer.

A 59-year-old man underwent submandibular gland excision for salivary duct carcinoma (SDC). One year later, esophagogastroduodenoscopy indicated gastric diffuse mucosal thickening with luminal contraction, mimicking scirrhous gastric carcinoma. Biopsy specimens showed dense proliferation of neoplastic cells expressing androgen receptor and human epidermal growth factor 2, indicating SDC. Gastric diffuse infiltrative metastasis is generally characteristic of gastric metastasis from invasive ductal carcinoma, which shows histologic features similar to SDC. This is the first known report of gastric diffusely infiltrating metastasis in an SDC patient. Rapidly progressing, diffuse gastric wall thickening should also be considered indicative of salivary tumor-associated gastric metastasis.

Salivary Duct Carcinoma Arising in a Warthin Tumor of the Parotid Gland: A Rare Case Report with Review of Literature and PD-L1 Expression.

Warthin's tumor is the second most common neoplasm of the parotid gland and consists of 2 components, including lymphoid stroma and glandular epithelium. Malignant transformation in this tumor is mostly seen in the lymphoid component; however, the carcinomatous transformation of the epithelial component is extremely rare. Cases of latter reported in the literature include squamous cell carcinoma, adenocarcinoma, mucoepidermoid carcinoma, oncocytic carcinoma, Merkel cell carcinoma, and undifferentiated carcinoma. We describe an extremely rare case of salivary duct carcinoma arising in a Warthin tumor in a 64-year-old male. Patient presented with an enlarging left parotid mass, biopsy of which showed salivary duct carcinoma. He subsequently underwent left parotidectomy along with left level II-IV lymph node dissection. Histology revealed both in situ as well as invasive salivary duct carcinoma arising from Warthin tumor. Immunohistochemistry showed tumor cells positive for CK7, AR, and GATA3, while p63 highlighted the myoepithelial cell layer in the in situ component. Her2 was 2+ by immunohistochemistry. In addition, PD-L1 IHC revealed positive expression with a combined positive score of 20%.

Radiologically-guided balloon sialoplasty for benign salivary duct obstruction: a 7-year UK service evaluation.

Obstructive sialadenitis is the most common cause of non-malignant salivary gland disorders, with salivary gland strictures being responsible for approximately 23% of all benign obstructive disease. Significant advances in minimally invasive techniques, including radiologically-guided balloon sialoplasty, offer the potential for successful treatment with reduced complications. At present there is a paucity of follow-up data regarding patient outcomes and repeat interventions in those undergoing the procedure. Patients with parotid or submandibular gland sialadenitis secondary to gland stricture were identified and underwent radiologically-guided balloon sialoplasty at Queen Alexandra Hospital, Portsmouth, UK between 2015 and 2022. Patient outcomes, complications and reintervention rates were recorded prospectively over the seven-year period and analysed retrospectively. A total of 44 patients underwent radiologically-guided balloon sialoplasty. Forty (89%) underwent sialoplasty for parotid gland disease, with a minority (n = 5) receiving an intervention for submandibular gland strictures. A total of 37 (84%) had their obstruction successfully treated (82% of parotid gland obstructions and 100% of submandibular gland obstructions). Five patients (11%) required a repeat intervention. Seventeen successfully treated patients (85%) who attended follow-up clinic appointments described complete resolution of their symptoms, with the remaining three (15%) describing a partial response. Radiologically-guided balloon sialoplasty for the treatment of benign obstructive sialadenitis secondary to a gland stricture is a safe and effective method of eliminating the obstruction and relieving patients' symptoms. Most patients were symptom free at short-term follow up, with a minority requiring a second sialoplastic intervention.

Transoral removal of submandibular hilar lithiasis: results on the salivary duct system, glandular parenchyma, and quality-of-life recovery.

OBJECTIVE(S): To confirm that hilar transoral submandibular sialolitectomy (TOSL) is the first treatment option for submandibular hilar lithiasis (SHL) in terms of glandular parenchyma recovery, salivary system restoration, and patient quality of life (QoL) improvement. METHODS: Depending on whether the stone was easily palpable, TOSL was carried out with or without sialendoscopy. For the first time in the literature, Magnetic Resonance Sialography (MR-Si) was performed before and after TOSL, to evaluate stone characteristics, glandular parenchyma status, hilum dilation and main duct recanalization. Radiological data was examined independently by two radiologists. COSQ, a recently validated and specific questionnaire, was used to assess associated QoL. RESULTS: Between 2017 and 2022, 29 TOSL patients were examined. With a high interobserver correlation, MR-Si was confirmed as a very useful radiological test in the pre- and post-surgical evaluation of SHL. The salivary main duct was completely recanalized in all cases. The presence of lithiasis was found in 4 patients (13.8%). After surgery, the majority of patients (79.31%) had hilum dilation. There was a statistically significant improvement in parenchyma status, but no significant progression to glandular atrophy. After surgery, COSQ mean values always improved (22.5 to 4.5). CONCLUSIONS: TOSL is the ideal surgical technique for the management of SHL, resulting in improved parenchymal inflammatory changes, recanalization of Wharton's duct, and enhancement patients' QoL. As a result, before removing the submandibular gland, TOSL should be considered as the first treatment option for SHL.

Outline of Salivary Gland Pathogenesis of Sjögren's Syndrome and Current Therapeutic Approaches.

Sjögren's syndrome (SS) is an autoimmune disease characterized by the involvement of exocrine glands such as the salivary and lacrimal glands. The minor salivary glands, from which tissue samples may be obtained, are important for the diagnosis, evaluation of therapeutic efficacy, and genetic analyses of SS. In the onset of SS, autoantigens derived from the salivary glands are recognized by antigen-presenting dendritic cells, leading to the activation of T and B cells, cytokine production, autoantibody production by plasma cells, the formation of ectopic germinal centers, and the destruction of salivary gland epithelial cells. A recent therapeutic approach with immune checkpoint inhibitors for malignant tumors enhances the anti-tumor activity of cytotoxic effector T cells, but also induces SS-like autoimmune disease as an adverse event. In the treatment of xerostomia, muscarinic agonists and salivary gland duct cleansing procedure, as well as sialendoscopy, are expected to ameliorate symptoms. Clinical trials on biological therapy to attenuate the hyperresponsiveness of B cells in SS patients with systemic organ involvement have progressed. The efficacy of treatment with mesenchymal stem cells and chimeric antigen receptor T cells for SS has also been investigated. In this review, we will provide an overview of the pathogenesis of salivary gland lesions and recent trends in therapeutic approaches for SS.

Effect of HER2-targeted therapy on PDX and PDX-derived organoids generated from HER2-positive salivary duct carcinoma.

BACKGROUND: We previously established a patient-derived xenograft (PDX) model, patient-derived organoids (PDOs), and PDX-derived organoids (PDXOs) for salivary duct carcinoma (SDC). Using these models, this study examined the therapeutic effect of human epidermal growth factor receptor 2 (HER2) blockade on HER2-positive SDC. METHODS: The therapeutic effect of lapatinib was assessed in SDC PDXOs with regards to cell growth, receptor/downstream signaling molecule expression, phosphorylation levels, and apoptosis. Effect of lapatinib treatment was evaluated in vivo in SDC PDX mice. RESULTS: The siRNA knockdown of HER2 and lapatinib suppressed cell proliferation in SDC PDXOs. Lapatinib inhibited the phosphorylation of HER2 and its downstream targets, and induced apoptosis in SDC PDXOs. Lapatinib also significantly reduced tumor volumes compared with that of the control in SDC PDX mice. CONCLUSION: For the first time, we demonstrated the efficacy of anti-HER2 therapy in HER2-positive SDC using preclinical models of SDC PDX and PDXO.

Lymph node ratio-based prognostic model for risk stratification and individualized adjuvant therapy for postoperative major salivary duct carcinoma.

BACKGROUND: To investigate the value of lymph node ratio (LNR) for postoperative major salivary duct carcinoma (MSDC) and to establish a model for prognosis assessment and treatment optimization. METHODS: Data of MSDC were retrieved in public database, and prognostic factors were identified by univariate and multivariate analyses. A nomogram and risk stratification system were constructed. RESULTS: Four hundred and eleven eligible patients were included (training cohort vs. validation cohort: 287: 124). LNR ≥0.09 was associated with worse overall survival (OS). Age at diagnosis, sex, T stage, and LNR were identified as prognostic factors and integrated into nomogram. Low-risk patients were found to have better OS than high-risk patients. Furthermore, postoperative radiotherapy (PORT) significantly improved OS in the high-risk subgroup, but chemotherapy did not confer a long-term survival benefit. CONCLUSIONS: A nomogram model integrating LNR could better assess postoperative prognosis and risk stratification in MSDC, and identify patients who might benefit from PORT to avoid overtreatment.

Myoepithelial Carcinoma Arising in a Salivary Duct Cyst of the Parotid Gland: Case Presentation.

Cystic lesions observed in parotid glands are relatively rare and comprise 2-5% of all parotid primaries. A salivary duct cyst (SDC) is a true cyst representing 10% of all salivary gland cysts. The risk of malignant transformation of SDC's epithelium is extremely rare. In the literature, only three cases of carcinoma ex SDC of the parotid gland are described. This report presents the first in the literature case of myoepithelial carcinoma (MECA) arising from a parotid SDC. A 75-year-old male patient was referred to the Department of Cranio-Maxillofacial Surgery of the Jagiellonian University in Cracow, Poland due to a cystic tumor arising from the right parotid gland. Superficial parotidectomy with facial nerve preservation was performed. Histological examination confirmed a rare case of MECA emerging from the SDC. The immunohistochemical profile of MECA ex SDC was presented. During 6 months of the follow-up, local recurrence or distant metastasis was not observed.

Prognostic models for estimating survival of salivary duct carcinoma: a population-based study.

PURPOSE: In a large salivary duct carcinoma (SDC) cohort, we aimed to investigate the clinical factors influencing their survival outcomes and to further establish prognostic models. METHODS: Data of patients with SDC were extracted from the Surveillance, Epidemiology, and End Results database (1975-2019). A retrospective analysis was conducted to explore the prognostic factors on overall survival (OS) and disease-specific survival (DSS), and corresponding nomograms were established. RESULTS: A steady upward trend in the incidence of SDC was observed over the past four decades. Totally, 399 patients (280 in the training set and 199 in the testing set) were enrolled. Advanced T stage, lymph node metastasis, distant metastasis, and surgery were associated with favorable OS and DSS. Besides, age > 80 years exhibited worse OS. The selected variables above were used to construct nomograms and online web calculators that could accurately predict patient survival. In addition, risk stratification systems were generated to identify low- and high-risk patients. As the risk level increased, the risk of both patient mortality and disease-specific mortality increased. CONCLUSIONS: The SDC incidence was low, but steadily increasing. The proposed prognostic models provided a robust and efficient approach to predict survival and risk stratification in SDC patients.

A Case of Metastatic Submandibular Salivary Duct Carcinoma that Completely Responded to Pembrolizumab Monotherapy.

Salivary gland carcinoma is a rare cancer and has more than 20 histopathological types. Although chemotherapy has been the mainstay of treatment for unresectable carcinomas such as multiple recurrence and distant metastasis, no standard regimen is available. In this article, we report a case of poorly differentiated salivary duct carcinoma of the submandibular gland with distant metastases that was successfully treated with pembrolizumab monotherapy. A 66-year-old man became aware of a left submandibular mass 2 months before his first visit to our department. A needle biopsy at a previous hospital revealed carcinoma, not otherwise specified. The combined positive score on a programmed death ligand-1 immunohistochemistry test was 1-10%. The patient was referred to our department for further treatment. Computed tomography revealed left level II and IV neck lymphadenopathy, bilateral lung shadowing, and osteolytic changes in the 12th thoracic vertebra. Needle biopsy showed poorly differentiated carcinoma, positive human epidermal growth factor receptor 2, and positive androgen receptor, which suggested salivary duct carcinoma. These findings indicated a diagnosis of submandibular carcinoma T4aN2bM1 stage IVC. Pembrolizumab monotherapy was started, and tumor shrinkage was observed after three courses of treatment. At 1 year, complete response was achieved without adverse events, and treatment is ongoing. Despite a lack of evidence for the efficacy of immune checkpoint inhibitors in salivary gland carcinoma, the present case suggests that some patients might respond to this treatment. Hence, clinical trials are warranted.

A Subset of Salivary Intercalated Duct Lesions Harbors Recurrent CTNNB1 and HRAS Mutations: A Molecular Link to Basal Cell Adenoma and Epithelial-Myoepithelial Carcinoma?

BACKGROUND: Intercalated duct lesions (IDLs) are benign salivary gland proliferations that resemble normal intercalated ducts and are subdivided into hyperplastic, adenoma or hybrid types depending on circumscription. While IDLs were historically regarded as non-neoplastic, frequent association with basal cell adenoma (BCA) and epithelial-myoepithelial carcinoma (EMC) has raised the possibility that they are neoplastic precursors. METHODS: In this study, we performed ß-catenin immunohistochemistry and targeted molecular analysis on IDLs to clarify their pathogenesis. RESULTS: We identified 15 IDLs from the parotid glands of eight men and six women with a median age of 65 years (range 42-85 years). These lesions included nine hyperplastic, three adenoma, and three hybrid types. Nuclear ß-catenin localization was present in 7 of 13 lesions tested (54%). Next generation sequencing was successfully completed in 12 IDLs, of which seven (58%) had likely oncogenic mutations. These included three recurrent CTNNB1 mutations in hyperplastic (n = 2) and hybrid (n = 1) lesions and two recurrent HRAS hotspot mutations in adenomas. CONCLUSION: Despite substantial heterogeneity, these findings confirm that a majority of IDLs are genuinely neoplastic, and some demonstrate molecular overlap with both BCA and EMC, supporting their theorized role as precursors to these tumors. Nevertheless, no oncogenic drivers were present in a significant subset of cases, suggesting that some IDLs may be truly reactive and hyperplastic. As such, IDL appear to represent a diverse morphologic and molecular spectrum that include both neoplastic and hyperplastic lesions. Reconsideration of the boundary between IDL and BCA in the future may be necessary to simplify classification.

Chronic Obstructive Sialadenitis due to an Abnormal Wharton's Duct Draining to the Tonsillar Fossa.

INTRODUCTION: Chronic obstructive sialadenitis (COS) is an entity that causes a marked loss in patient quality of life, including changes in eating habits and a progressive loss of gland function. It is characterized by repeated episodes of painful glandular swelling often requiring emergency care. There are multiple causes of COS, including lithiasis, strictures, anatomical variants, and others. The development of specific imaging tests such as magnetic resonance (MR) sialography or sialendoscopy have increased knowledge of these obstructions and how to specifically treat them. CASE SUMMARY: We present an unusual case of a woman with a years-long history of chronic obstructive sialadenitis in which an abnormal path of Wharton's duct was in evidence. This duct, which was atrophic and smaller in diameter, opened in the tonsillar fossa rather than lateral to the lingual frenulum. This case, the first in vivo description of its kind, was confirmed by MR sialography and sialendoscopy. DISCUSSION: Congenital anomalies of the submandibular duct are a rare finding, but may cause COS. Therefore, COS requires a detailed diagnostic study, usually by ultrasound, MR sialography and sialendoscopy, to rule out complex anatomical variants.

Role of HER2 in Prognosis of Salivary Duct Carcinoma: A Systematic Review and Meta-Analysis.

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare, aggressive malignancy with a poor prognosis. These tumors frequently stain positive for HER2/ErbB2, but data on the prognostic significance of HER2 status in SDC are mixed. We sought to determine whether HER2 status affects survival outcomes in SDC. METHODS: PubMed, Embase, and Web of Science databases were searched from inception to October 2020. Eligibility was restricted to studies reporting HER2/ErbB2 overexpression in histologically confirmed de novo SDC or SDC ex pleomorphic adenoma, with corresponding overall (OS) and disease-free (DFS) survival measures. Separate multivariable and univariable meta-analyses were performed using random-effects models. Statistical heterogeneity was estimated by Cochran's Q and I2 tests. Funnel plots were generated and Egger's test was used to assess for publication bias. The risk of bias was assessed with the Newcastle-Ottawa Scale. RESULTS: Of 183 unique citations, 14 studies of 663 patients were included. Most included studies determined HER2 status according to ASCO/CAP guidelines. The univariable meta-analysis did not reveal an effect between HER2 status and OS (HR 1.09, 95% CI 0.84-1.42). In the multivariable analysis, HER2 positivity was associated with a HR of 1.49 for OS (95% CI 0.96-2.30). Fewer studies reported data for DFS than OS, with no relationship between HER2 status and DFS found on multivariable or univariable meta-analyses. CONCLUSION: In patients with salivary duct carcinoma, HER2 positivity was not found to be associated with worse overall survival. This information may be useful when counseling patients and considering treatment options. Laryngoscope, 133:476-484, 2023.

The Role of Sialendoscopy in Parotid Duct Stenosis in Graft-Versus-Host Disease.

Sialendoscopy, a minimally invasive procedure for concurrent diagnosis and treatment of salivary gland ductal pathologies, was used to alleviate recurrent left parotid gland swelling and dry mouth in a 58-year-old man with chronic graft-versus-host disease. Laryngoscope, 133:279-281, 2023.