The extent of androgen receptor and HER2 expression allows for targeted therapy in most cases of salivary duct carcinoma: analysis of clinical and histopathological data in a tertiary care center.

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.

MR sialographic assessment of the masseter muscle and the ductal kinking in patients with recurrent parotitis.

Dysfunction of the masseter muscle may cause pathological kinking of the parotid duct leading to parotitis; MR sialography is a non-invasive radiological examination that allows to evaluate dynamically the ductal system of the parotid glands. In the present study we aimed to assess the relationships between Stensen's duct and masseter muscle and their implications in the aetiopathogenesis of recurrent parotitis secondary to masseter muscle dysfunction. Forty-one patients with recurrent unilateral parotitis and nine with bilateral recurrent parotitis, all with a clinical suspicious of masseter muscle hypertrophy due to bruxism were enrolled. They underwent ultrasonography as a first line examination and then MR sialography and sialendoscopy. Different anatomical features were studied. Involved parotid glands had a wider duct compared to contralateral unaffected parotid glands of patients with recurrent parotitis (p = 0.00134); male subjects with parotitis had a longer duct compared to the salivary glands of healthy patients (p = 0.00943 for affected glands and p = 0.00629 for the contralateral). A concordance between the evidence of an acute duct angle during sialendoscopy and a wider duct in patients with parotitis was observed although not statistically significant. These initial findings suggest that the masticatory muscle dysfunction related to bruxism seems to condition alteration of parotid duct course and anatomy thus favouring the occurrence of recurrent parotitis. A specific diagnostic iter based on clinical evaluation, dynamic ultrasonography and MR sialography, is therefore, mandatory to confirm the relationship between masseter muscle anatomy and parotid duct anomalies; this is the premise for an adequate therapeutic approach to underlying masticatory muscle disorder.

The anterior lobe of the parotid gland: a CT sialographic study.

OBJECTIVES: To investigate the imaging and anatomic features of the anterior lobe (AL) of the superficial parotid gland (SPG). METHODS: Computed tomographic sialography examinations were undertaken for 142 parotid glands in 77 patients. Whole computer tomography (CT) data were analyzed using multi-planar reformation and maximum intensity projection to generate sialographic CT images. The tributary ducts of the SPG were analyzed to classify the parotid morphology. Three-dimensional analyses were used to investigate the AL and its relationship with adjacent anatomic landmarks. RESULTS: Four major types (I-IV) and 2 minor types (V-VI) of the AL and the superficial parotid gland were observed. Type I AL (83/142) was contiguous and not separated from the retromandibular parotid gland. Type II AL (16/142) was detached from the retromandibular parotid gland with 1-4 tributary ducts. Type III AL (12/142) showed a small isolated lobe above the Stensen duct around the anterior edge of the masseter. Type IV (28/142) showed the absence of the AL. Type V (3/142) shows the absence of the retromandibular parotid gland. Type VI (3/142) showed the presence of ectopic salivary gland beneath the Stensen duct anterior to the retromandibular parotid gland. CONCLUSIONS: The AL gives rise to the morphological variations of the superficial parotid gland. AL also gives rise to the accessory parotid gland when it is detached from the retromandibular parotid gland.

Comparative analysis of approaches to the Wharton's duct during surgery of the submandibular gland: A retrospective case-control study.

INTRODUCTION: We investigated complications and recurrence rates after surgical techniques for sialolith removal with intact and resected Wharton's duct of the submandibular gland. METHODS: The retrospective case-control analysis of a series analysed 271 surgical operations (2003-2022) for sialolithiasis performed at a hospital department of Otolaryngology-Head and Neck Surgery. The study compared two approaches: (1) pure endoscopic technique or pinpoint stone removal with Wharton's duct left intact and (2) transoral duct dissection or pinpoint stone removal technique, after which the duct was shortened. While choosing the surgical option, the size of the stone, the location of the stone, and the presence of multiple stones were taken into account. The rates of complications (lingual nerve paraesthesia, duct stenosis, drooling, and sialoadenitis), the incidence of foreign bodies, and the rate of recurrence during follow-up of ≥18 months were compared. RESULTS: 323 sialoliths were removed from 271 patients. Of these 323 calculi, 150 were removed by the first approach and 173 by the second approach. The calculi varied in diameter from 2 to 38 mm with an average diameter of 8.2 mm. For all 271 patients, the rate of recurrence was 4.8%, but 11 recurrent cases (8.7%) appeared after the first approach surgeries and 2 cases (1.4%) after the second approach surgeries (p = .03). Other variables did not show statistically significant differences. CONCLUSIONS: Surgical removal of the submandibular calculi, ending with shortening of Wharton's duct, reduces the recurrence rate for sialolithiasis but does not affect the rate of postsurgical complications.

Intraglandular Foreign Body - Unusual Aetiology of Submandibular Gland Sialadenitis.

Obstructive sialadenitis of submandibular gland is commonly due to sialoliths and strictures in the Wharton's duct. Other endogenous pathologies include mucous plugs and polyps. Foreign bodies of Wharton's duct and submandibular gland are rare. Retrograde migration of foreign bodies via ductal orifice, traversing the ductal system to its final intraglandular location is an even rare entity. These often present with painful swelling of the gland and at times with a purulent sialitis. Diagnostic modalities include plain radiography, ultrasonography, sialography, as well as computed tomography and magnetic resonance imaging. Treatment includes antibiotics, incision and drainage of abscess, and removal of foreign body either surgically (intra-oral approach or sialadenectomy) or more recently via sialoendoscopy. This is a case report of 30 years male with accidental cannulation of Wharton's duct with grass that eventually got lodged in the deep lobe of the gland, and was managed with sialadenectomy.

Adjuvant Radiation Therapy for Salivary Duct and Epithelial Myoepithelial Salivary Carcinoma.

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.

Specific localization of fibroblasts at the intercalated duct in the major salivary glands of rats.

OBJECTIVES: Immunohistochemical methods were employed to investigate the morphological heterogeneity and localization of fibroblasts associated with the function of major salivary glands in rats. METHODS: Histochemical and electron microscopic observations were made in rat parotid, submandibular, and sublingual glands and pancreas. Fibroblasts were immunostained using their specific marker, 47 kDa heat shock protein (Hsp47). RESULTS: Hsp47-immunopositive fibroblasts within the intralobular connective tissue exhibited a notably smaller size compared with the interlobular connective tissue. They were loosely distributed throughout the connective tissue. However, fibroblasts with elongated long processes were explicitly identified at the intercalated ducts in parotid, sublingual, and submandibular glands. Fibroblastic bodies and processes were tightly approximated with the basement membrane of the duct. Electron microscopy confirmed these findings, revealing a thin layer consisting of collagen fibers was found between the fibroblasts and the basement membrane. Double staining of Hsp47 and α-smooth muscle actin (αSMA) in parotid glands indicating that Hsp47-positive fibroblasts enveloped both the duct and αSMA-positive myoepithelial cells. Additionally, They projected long and thin processes longitudinally at the straight portion or circularly at the bifurcated portion of the duct. The three-dimensional reconstruction showed a frame-like structure of fibroblasts surrounding the intercalated duct with longitudinal myoepithelial cells. However, such specific localization of fibroblasts was not detected in the exocrine pancreas lacking myoepithelium. CONCLUSIONS: Small fibroblasts with long processes connecting or overwrapping each other and thin collagen layers surround the intercalated ducts in rat major salivary glands, presumably contributing to protecting the ducts from salivary flow and myoepithelial contraction.

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.

Fingertip cutaneous metastasis of salivary duct carcinoma secondary to scald: A unique case report and a brief review of literature (following CARE guidelines).

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.

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.

Muscarinic acetylcholine receptor-mediated phosphorylation of extracellular signal-regulated kinase in HSY salivary ductal cells involves distinct signaling pathways.

OBJECTIVES: Typical agonists of G protein-coupled receptors (GPCRs), including muscarinic acetylcholine receptors (mAChRs), activate both G-protein and ß-arrestin signaling systems, and are termed balanced agonists. In contrast, biased agonists selectively activate a single pathway, thereby offering therapeutic potential for the specific activation of that pathway. The mAChR agonists carbachol and pilocarpine are known to induce phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2) via G-protein-dependent and -independent pathways, respectively. We investigated the involvement of ß-arrestin and its downstream mechanisms in the ERK1/2 phosphorylation induced by carbachol and pilocarpine in the human salivary ductal cell line, HSY cells. METHODS: HSY cells were stimulated with pilocarpine or carbachol, with or without various inhibitors. The cell lysates were analyzed by western blotting using the antibodies p44/p42MAPK and phosphor-p44/p42MAPK. RESULTS: Western blot analysis revealed that carbachol elicited greater stimulation of ERK1/2 phosphorylation compared to pilocarpine. ERK1/2 phosphorylation was inhibited by atropine and gefitinib, suggesting that mAChR activation induces transactivation of epidermal growth factor receptors (EGFR). Moreover, inhibition of carbachol-mediated ERK1/2 phosphorylation was achieved by GF-109203X (a PKC inhibitor), a ßARK1/GRK2 inhibitor, barbadin (a ß-arrestin inhibitor), pitstop 2 (a clathrin inhibitor), and dynole 34-2 (a dynamin inhibitor). In contrast, pilocarpine-mediated ERK1/2 phosphorylation was only inhibited by barbadin (a ß-arrestin inhibitor) and PP2 (a Src inhibitor). CONCLUSION: Carbachol activates both G-protein and ß-arrestin pathways, whereas pilocarpine exclusively activates the ß-arrestin pathway. Additionally, downstream of ß-arrestin, carbachol activates clathrin-dependent internalization, while pilocarpine activates Src.

Nivolumab as a Promising Treatment Option for Metastatic Salivary Duct Carcinoma.

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.

Capecitabine is effective as palliative chemotherapy in a patient with androgen receptor and HER2 positive metastatic salivary duct carcinoma. A case report.

ABSTRACT: Metastatic salivary duct carcinomas (SDC) are rare tumors and evidence-based guidelines for their treatment have not yet been established. Reports of such cases like ours could be beneficial in the decision-making in the similar clinical circumstances. Here we present the 64-year-old Caucasian man with bone pain and pancytopenia two years after local treatment of SDC, in whom a bone marrow biopsy revealed poorly differentiated carcinoma of salivary origin with nuclear androgen receptor (AR) and human epidermal growth factor receptor 2 (HER2/neu) positivity. Clinical response was achieved with cis-platin based cytotoxic therapy and maintenance hormonal treatment. At progression after 12 months, he was treated with anti-HER2 therapy combined with taxanes. The response lasted for 14 months. Then palliative therapy with capecitabine was introduced. With a relatively sustained quality of life, the response lasted for 15 months.

Recent progress in the treatment of intractable sialolithiasis / 北京大学学报(医学版)

Sialolithiasis occurs in approximately 0.45% to 1.20% of the general population. The typical clinical symptom manifests as a painful swelling of the affected glands after a meal or upon salivary stimulation, which extremely affects the life quality of the patients. With the development of sialendoscopy and lithotripsy, most sialoliths can be successfully removed with preservation of the gland. However, sialoliths in the deep hilar-parenchymal submandibular ducts and impacted parotid stones located in the proximal ducts continue to pose great challenges. Our research center for salivary gland diseases (in Peking University School and Hospital of Stomatology) has used sialendoscopy for 17 years and treated >2 000 patients with salivary gland calculi. The success rate was approximately 92% for submandibular gland calculi and 95% for parotid calculi. A variety of minimally invasive surgical techniques have been applied and developed, which add substantial improvements in the treatment of refractory sialolithiasis. Further, the radiographic positioning criteria and treatment strategy are proposed for these intractable stones. Most of the hilar-parenchymal submandibular stones are successfully removed by a transoral approach, including transoral duct slitting and intraductal basket grasping, while a small portion of superficial stones can be removed by a mini-incision in submandibular area. Impacted stones located in the distal third of parotid gland ducts are removed via "peri-ostium incision", which is applied to avoid a cicatricial stenosis from a direct ostium incision. Impacted parotid stones located in the middle and proximal third of the Stensen's duct are removed via a direct mini-incision or a peri-auricular flap. A direct transcutaneous mini-incision is commonly performed under local anesthesia with an imperceptible scar, and is indicated for most of impacted stones located in the middle third, hilum and intraglandular ducts. By contrast, a peri-auricular flap is performed under general anesthesia with relatively larger operational injury of the gland parenchyma, and should be best reserved for deeper intraglandular stones. Laser lithotripsy has been applied in the treatment of sialolithiasis in the past decade, and holmium ∶YAG laser is reported to have the best therapeutic effects. During the past 3 years, our research group has performed laser lithotripsy for a few cases with intractable salivary stones. From our experiences, withdrawal of the endoscopic tip 0.5-1.0 cm away from the extremity of the laser fiber, consistent saline irrigation, and careful monitoring of gland swelling are of vital importance for avoidance of injuries of the ductal wall and the vulnerable endoscope lens during lithotripsy. Larger calculi require multiple treatment procedures. The risk of ductal stenosis can be alleviated by endoscopic dilation. In summary, appropriate use of various endoscopy-assisted lithotomy helps preserve the gland function in most of the patients with refractory sialolithiasis. Further studies are needed in the following aspects: Transcervical removal of intraglandular submandibular stones, intraductal laser lithotripsy of impacted parotid stones and deep submandibular stones, evaluation of long-term postoperative function of the affected gland, et al.

Sialoendoscopia y abordaje mixto para el manejo dela patología obstructiva de las glándulas salivales / Sialoendoscopy and mixed approach for the management of obstructive pathology of the salivary glands

Introducción. La sialoendoscopia es un procedimiento cuya finalidad es visualizar los conductos salivales. Se utiliza como método diagnóstico y terapéutico de procesos inflamatorios, estenosis de los conductos y procesos obstructivos. Métodos. Describir los procedimientos realizados para el tratamiento de pacientes con patología inflamatoria y obstructiva de las glándulas salivales, de forma única con sialoendoscopia o con abordajes mixtos. Resultados. Un total de 24 pacientes fueron incluidos en el estudio, con edad promedio de 42 años, en su mayoría mujeres y compromiso submaxilar en 58,3 % y de parótida en 41,7 %. Respecto a la intervención, al 29,2 % de los sujetos se le realizó extracción de cálculos, al 29,2 % sialoplastia, al 25 % dilatación de conductos y al 37,5 % lavado de conductos en el mismo momento quirúrgico. Conclusión. La sialoendoscopia y el abordaje mixto es un procedimiento que puede garantizar el manejo de patologías obstructivas y estenosis de los conductos salivales, con buen pronóstico y resultados, preservando la glándula y evitando las complicaciones de la cirugía.

Introduction. Sialoendoscopy is a procedure which purpose is to visualise the salivary ducts. It is used as a diagnostic and therapeutic method for inflammatory and obstructive processes and duct stenosis. Methods. To describe the procedures performed for the management of patients with inflammatory and obstructive pathology of the salivary glands, only with sialoendoscopy or with mixed approaches. Results. A total of 24 patients were included in the study, with mean age of 42 years, mostly female, and 58.3% submaxillary involvement 41.7% parotid involvement. Regarding the intervention, 29.2% of the subjects underwent stone extraction, 29.2%, sialoplasty, 25% duct dilatation, and 37.5% duct lavage at the same surgical time. Conclusions. Sialoendoscopy and the mixed approach is a procedure that can guarantee the management of obstructive pathologies and stenosis of the salivary ducts with good prognosis and results, preserving the gland and avoiding the complications of surgery.

Primary lung salivary gland-type duct carcinoma: a clinicopathological analysis of two cases and review of literature / 中华病理学杂志

Objective: To investigate the clinicopathological features, diagnostic criteria and differential diagnosis of primary salivary gland-type duct carcinoma of lung(LSDC). Methods: Two patients with LSDC after surgical resection in Shanghai Pulmonary Hospital from 2020 to 2021 were included; their clinical parameters as well as pathological, immunohistochemical and molecular characteristics of the tumors were analyzed. The relevant literature was also reviewed. Results: Both patients were male, aged 49(case 1) and 64(case 2) years, respectively, and with a history of smoking. The chest computed tomography scan showed both lesions to be centrally located. Gross examination showed the maximum diameters were 16 mm and 35 mm, respectively. The histomorphology of LSDC resembled ductal carcinoma of breast, with intraductal islands of neoplastic cells, which also formed solid nests, papillary, micropapillary and cribriform structures. There was frequent accompanying comedo-like necrosis. The neoplasm cells were markedly heteromorphic, possessing large irregular nuclei with prominent nucleoli, abundant eosinophilic or clear cytoplasm, and mitotic figures were common. Both cases of LSDC were immunoreactive for CKpan, CK7, AR, HER2 staining was (2+) and were negative for TTF1, Napsin A, p40, GATA3, mammaglobin, GCDFP15, SOX10, PSA, P504S, ER, PR, vimentin, S-100, SMA, CK5/6 and p63. The tumor showed double-layer cell structure of the duct, and some basal cells/myoepithelial cells expressed p40 and CK5/6. Case 1 had no gene mutation while case 2 harbored TP53 and KMT2A gene mutation detected by next generation sequencing. Conclusions: LSDC is a very rare and highly aggressive salivary-type malignant tumor. The postoperative diagnosis mainly depends on histopathology and immunohistochemistry, attention should be paid to differential diagnosis to prevent missed diagnosis.