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Sialadenitis is a prevalent salivary gland disease resulting in decreased salivary flow rate. To date, little is known about the exact changes and mechanism of ductal cells in sialadenitis. This study aims to establish an efficient method to identify and isolate ductal cells, thereby facilitating further research on this specific cell type. Immunofluorescence for cytokeratin 13 and cytokeratin 19 was conducted in salivary glands to confirm their specificity as ductal cell markers. The dissected ducts were assessed through PCR and Western blot of cytokeratin 19 and digested by dispase and collagenase. The functionality of the isolated ductal cells was determined by measuring intracellular calcium. Cytokeratin 19 and cytokeratin 13 were expressed in all segments of human ducts. Cytokeratin 19 was limited to ducts excluding granular convoluted tubules in rat and mouse. The purities of the obtained ductal cells were approximately 98% in humans and 93% in rats. Furthermore, intracellular free calcium increased with time and concentration of carbachol treatment. Cytokeratin 19 serves as a dependable marker for identifying ductal cells in salivary glands, except for granular convoluted tubules. Moreover, we have successfully developed an efficient method for isolating ductal cells from salivary glands., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Warthin tumor (WT) is the second most common benign parotid gland tumor after pleomorphic adenoma. WT is characterized by cystic and papillary proliferation of a two-layered oncocytic epithelium supported by lymphoid tissue. Heterotopic salivary duct inclusions (SDIs) are frequently observed in lymph nodes (LNs) of WT (SDI/LNs), and are thought to be the origin of WT. If this is true, SDIs should also persist in the lymphoid tissue of WT itself (SDI/WT), as a missing link between SDIs and WTs, but studies of this issue are limited. From 2008-2023, 138 WT cases were surgically excised at our hospital. SDI/LNs and SDI/WTs were histologically examined. Of 100 WT cases with LNs, SDI/LNs were observed in 67 cases (67 %). SDI/WTs were detected in 114 of 138 cases (82.6 %), including 107 of 127 smokers (84.3 %) and 7 of 11 never-smokers (63.6 %). SDI/WTs were located mainly in the subcapsular lymphoid tissue and often surrounded by a fibrous coat resembling salivary excretory ducts. This study revealed a high incidence of SDIs in WT itself, strongly supporting the theory that WT develops from heterotopic salivary ducts., Competing Interests: Declaration of Competing Interest The authors have no competing interests to disclose., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive cancer-related disease with a dismal clinical course. The patient in this report was a 43-year-old man with metastatic salivary duct carcinoma arising from the parotid gland. Combined androgen blockade therapy was administered started as first-line treatment, but failed after 5 months, followed by docetaxel plus carboplatin therapy as second-line treatment, which failed after 3 months. Genomic profiling revealed a BRAF V600E mutation, and combined BRAF and MEK inhibitor therapy was started as third-line treatment. The cancer remained stable during the first 10 months of third-line treatment, but treatment was subsequently discontinued due to the onset of symptoms of fatigue, myalgia and arthritis. Twenty days after the onset of these symptoms and interruption of third-line treatment, the patient was urgently admitted to hospital with respiratory distress and severe thrombocytopenia. CT images at the time of admission led our radiologist to the possibility of PTTM, but the patient died the day after admission and autopsy findings indicated that PTTM was the cause of death. This report describes a very informative case of PTTM with sequential imaging and detailed autopsy findings were available and provides a literature review., Competing Interests: Declaration of competing interest Three of the authors (Yoshitaka Honma, Ken Kato, Masahiko Kusumoto) declare the following financial interests/personal relationships which may be considered as potential competing interests: 1) Yoshitaka Honma has received compensation as a member of the advisory role of Janssen, Eisai, and Rakuten Medical Japan; received honoraria from Novartis, Chugai pharma, MSD, Ono pharmaceutical, Bristol Myers Squibb, Merck Biopharma, Eisai, Eli Lilly, Nutri, Teijin pharma, Bayer, and Taiho pharmaceutical; and received research funding from Taiho pharmaceutical, Chugai pharma, MSD, GlaxoSmithKline, Janssen, Adlai Nortye Biopharma, Maruho, Merck Biopharma, Genmab, Astellas pharma, Rakuten Medical Japan, and AstraZeneca. 2) Ken Kato reports funding to the institution from Merck Sharp & Dohme Corp (MSD), Ono Pharmaceuticals, Bristol Myers Squibb (BMS), Beigene, Shionogi, Merck Biopharma, Oncolys BioPharma, Daiichi Sankyo, Novartis, Taiho Pharmaceutical, Janssen, AstraZeneca, and Chugai. 3) Masahiko Kusumoto received honoraria for lecture fees from Daiichi-Sankyo Co.,Ltd. Masahiko Kusumoto received a research grant from Canon medical systems corporation., (Copyright © 2024. Published by Elsevier B.V.)

Background and Aims: Salivary duct carcinoma (SDC) is an aggressive salivary malignancy with multiple morphological subtypes. Primary salivary squamous cell carcinoma (SCC) requires exclusion of high-grade salivary malignancies and metastatic disease and is considered exceptionally rare. We report six cases of SDC with resemblance to SCC on account of variable, but often extensive, squamous differentiation., Methods and Results: A retrospective review (2009-2023) at two institutions of SDC with histological and immunophenotypical evidence of squamous differentiation identified six cases. Medical charts and available glass slides were reviewed. There were five males and one female with a median age of 63 years, with tumours involving the parotid (five of six) and submandibular (one of six) glands. All six tumours showed a conventional SDC component comprising < 5-90% of viable tumour. Squamous differentiation comprised 10-95%+ (> 75% in three of six cases) of total viable tumour, and demonstrated CK5/6, p63 and/or p40 immunoexpression in all cases. A sarcomatoid component, comprising 10-60% of viable tumour, was present in three of six (50%) cases. All tumours were androgen receptor (AR)-positive, but only two of six (33.3%) retained AR immunoreactivity in the squamous component. Metastatic SDC to regional lymph nodes exhibited exclusive squamous differentiation in two of six (33.3%) cases., Conclusion: Squamous differentiation, histologically and immunophenotypically, can be extensive in SDC. AR expression may be lost in the squamous component and metastases may demonstrate only squamous differentiation. These findings cast further doubt on the existence of primary salivary SCC. SDC should be considered whenever encountering a carcinoma with squamous differentiation in major salivary glands or within cervical lymph nodes in the setting of a salivary mass., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Background: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients., Methods: This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome., Discussion: The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice., Trial Registration: Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022., Protocol Version: Current protocol version 4.0, February 21, 2024., (© 2024. The Author(s).)

Many researchers have focused on the role of the autonomic nervous system in the tumor microenvironment. Autonomic nerves include the sympathetic and parasympathetic nerves, which are known to induce cancer growth and metastasis. However, in salivary duct carcinoma (SDC), a rare and highly malignant tumor, the issue should be investigated from both biological and therapeutic perspectives. We explored the clinicopathological and prognostic implications of the autonomic nerves in 129 SDCs. Immunohistochemistry was performed to determine the nature of each nerve using antibodies against S100, tyrosine hydroxylase (TH) as a sympathetic marker, and vesicular acetylcholine transporter (VAChT) as a parasympathetic marker. The area of each marker-positive nerve was digitized and evaluated quantitatively. Double immunofluorescence for TH and VAChT was performed in selected cases. The expression of the secreted neurotrophins was also examined. S100-positive nerves were present in the cancer tissue in 94 of 129 cases (72.9%). Among them, TH-positive sympathetic nerves and/or VAChT-positive parasympathetic nerves were identified in 92 cases (97.9%), and 59 cases (62.8%) had TH/VAChT-co-expressing nerves. Double immunofluorescence revealed a mosaic pattern of sympathetic and parasympathetic fibers in co-expressing nerve bundles. The presence of autonomic nerves, regardless of their area, was significantly associated with aggressive histological features, advanced T/N classification, and a poor prognosis, with shorter disease-free and overall survival. There was an association between some tumor immune microenvironment-related markers and the autonomic nerve status, but not the latter and the secreted neurotrophin expression. This study suggests that autonomic nerves might play a role in the progression of SDC., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Salivary duct carcinomas (SDC) of the parotid gland are rarely occurring highly malignant tumors. A 65-year-old man presented with a preauricular mass. After surgical treatment and histologic examination, the findings were interpreted as a squamous cell carcinoma (SCC) metastasis of the parotid gland deriving from a cancer of unknown primary DD primary SCC of the parotid gland. Adjuvant platinum-based radiochemotherapy was administered in domo. However, re-staging revealed multiple size-progressive pulmonary round lesions. After resection and histological examination of a pulmonary mass and in synopsis with the primary tumor, the initial diagnosis of SCC was revised to SDC of the parotid gland. With positive HER-2 status, off-label trastuzumab/docetaxel was initiated in an individual healing attempt, during which the pulmonary metastases showed clear progression. Consequently, the patient received immunotherapy with nivolumab according to his negative PD-L1 status. After 57 cycles of nivolumab, the patient presents with partial remission and in good condition. We report, for the first time, a robust response of metastatic SDC to checkpoint inhibition with nivolumab without additional radiotherapy., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Salivary duct carcinoma (SDC) is an aggressive form of cancer, with cutaneous metastasis being a rare occurrence. Furthermore, cutaneous metastasis of SDC secondary to a scald is even rarer, and to the best of our knowledge, our case represents the first such instance. Considering the involvement of the fingers in the metastatic site, which may affect limb function and quality of life, we present this case to explore the reason why scald could lead to distant recurrence and better treatment options., Patient Concerns: An 85-year-old man diagnosed with SDC in the parotid gland found enlarged masses at the fingertips as a consequence of a burn, 6 years after his initial treatment., Diagnoses: Cutaneous metastasis of SDC in the parotid gland and left thumb loss due to surgery., Interventions: Radiotherapy was offered, targeting at the masses on the fingers, with dose at 15 Gy in 3 fractions, 12 Gy in 3 fractions, 15 Gy in 3 fractions for both hands and additional 21 Gy in 7 fractions only for left hand., Outcomes: The tumors shrank after 2 months of radiotherapy and the patient recovered well. Side effects included nail hyperplasia and paronychia., Lessons: Connections between scald and distant metastasis of malignant tumors in this case needed further investigation. Considering reserving function of the fingers while dealing with metastasis, radiotherapy is recommended rather than surgery., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Salivary gland cancers are rare in general and salivary duct carcinoma and epithelial myoepithelial carcinomas are rare subtypes. This topic discussion will review the characteristics of these uncommon cancers. Additionally, it will briefly discuss available guidelines for salivary cancers and summarize author opinions on the role of adjuvant radiation therapy for these cases., Competing Interests: Disclosures None., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objective: To analyse the histopathological features of eosinophilic sialodochitis by using terminal duct biopsy., Methods: Sixty-five patients with suspected eosinophilic sialodochitis and four with chronic obstructive sialadenitis were prospectively enrolled. Clinical features, laboratory tests and sialograms were comparatively analysed. Terminal duct biopsy of the parotid or submandibular glands was performed concomitantly with endoscopy-assisted duct dilatation to determine the histopathological features of eosinophilic sialodochitis., Results: Based on eosinophil quantification, the samples of suspected patients were scored as 'definite', 'highly suspected' and 'negative' in 26 (40%), 15 (23.1%) and 24 (36.9%) cases, respectively. Gland types and peripheral blood eosinophil counts were significantly different among these three groups. The proportions of itching glands, mucus plug exudations and elevated immunoglobulin E levels were higher in the 'definite' group than in the other two groups; however, the intergroup differences were insignificant. The primary pathological features of eosinophilic sialodochitis were abundant eosinophils and lymphocytes infiltrated around the duct, degranulation of eosinophils, extensive fibrosis and scattered mastocytes. Periductal eosinophils were not found in cases of chronic obstructive sialadenitis., Conclusion: Our findings suggest that terminal duct biopsy is safe and valuable for the pathological confirmation of eosinophilic sialodochitis, and can be used simultaneously with endoscopy-assisted duct dilatation., (© 2023 Wiley Periodicals LLC.)

Purpose: 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., (© 2024. The Author(s).)

Objective: The aim of this communication was to introduce a novel combined image (magnetic resonance and computed tomography-guided and sialendoscopy-assisted transoral approach for the treatment of a parotid duct stenosis with megaduct., Methods: A 46-year-old woman was referred to our department for recurrent infections of the right parotid gland following unsuccessful multiple transoral surgical approaches for a Stensen's duct stricture with megaduct. An image (magnetic resonance and computed tomography)-guided and sialendoscopy-assisted transoral sialodochoplasty was planned and performed., Results: No complications occurred. The patient was discharged 2 days after surgery. No more swelling or infections occurred. The patient is currently symptom-free after a follow up of 11 months., Conclusion: Although imaging navigation means more technical effort and costs, this novel approach can be considered a viable surgical opportunity for distal and mid-third parotid duct stenosis with concomitant megaduct, particularly in cases of persistent inflammation or iatrogenic scars due to previous surgery.

Aims: To investigate the clinicopathological features, molecular characteristics and diagnostic criteria of primary salivary duct carcinoma of the lung (LSDC)., Methods: We analysed the clinicopathological and molecular features of five cases of LSDC retrieved from the archives of Shanghai Pulmonary Hospital from 2020 to 2022, and reviewed the relevant literature., Results: All patients were men, with an average age of 66 years (age range: 49-79 years), and all lesions were central masses with a mean maximum diameter of 42.6 mm (range: 16-70 mm). Morphologically, LSDC comprised of intraductal and invasive components. Both the intraductal and invasive components of LSDC can exhibit papillary, micropapillary, cribriform, tubule structures and solid proliferation. The intraductal component can exhibit Roman bridge structures, which were usually accompanied by central comedo-like necrosis. Immunohistochemically, LSDCs consistently expressed cytokeratin (CK)7 (5 of 5) and showed variable positivity of androgen receptor (AR) (5 of 5) focally or diffusely; additionally, the tumour cells expressed human epidermal growth factor receptor 2 (HER2) (3+, n=3; 2+, n=2), GATA-binding protein 3 (3 of 5), and gross cystic disease fluid protein-15 (1 of 5), and all of which were negative for thyroid transcription factor-1, napsin A, p40, CK5/6 and p63. The residual basal/myoepithelial cells surrounding the in situ carcinoma expressed p40, CK5/6 and p63. TP53 mutation and HER2 gene amplification (3 of 5) were the most frequent genetic alterations in LSDC. All patients who underwent surgical lobectomies were alive without recurrence or metastasis., Conclusions: LSDC is a highly rare malignant tumour. The distinctive architecture of in situ carcinoma and tumour cells expressing AR can provide diagnostic indications for LSDC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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.