Systemic therapy in the management of recurrent or metastatic salivary duct carcinoma: A systematic review

BackgroundSalivary duct carcinoma (SDC) is an aggressive subtype of salivary gland cancer. Approximately half of SDC patients will develop recurrences or metastases. Therapeutic palliative therapy is therefore often needed. The majority of SDC tumors expresses the androgen receptor (AR) and one-third expresses human epidermal growth factor receptor 2 (HER2), both are potential therapeutic targets. The aim of this paper is to systematically review and summarize the evidence on systemic palliative therapy for SDC and to provide treatment recommendations.Materials and methodsElectronic libraries were systematically searched with a broad search strategy to identify studies where SDC patients received systemic therapy. Due to the rarity of SDC no restrictions were placed on study designs.ResultsThe search resulted in 2014 articles of which 153 were full-text analyzed. Forty-five studies were included in the analysis, which included in total 256 SDC patients receiving systemic therapy. Two phase 2 trials primarily including SDC patients were identified. The majority of the studies were case series or case reports, resulting in an overall low quality of available evidence. Based on studies including ≥ 5 SDC patients, objective responses to HER2 targeting agents were observed in 60–70%, to AR pathway agents in 18–53% and to chemotherapy in 10–50%.ConclusionFor AR or HER2 positive SDC, agents targeting these pathways are the cornerstone for palliative treatment. Regarding chemotherapy, the combination of carboplatin combined with a taxane is best studied. Regarding other targeted agents and immunotherapy evidence is anecdotal, limiting formulation of treatment recommendations for these antineoplastic agents.     

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact

BackgroundPre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and β, RET, KIT).Patients and methodsPatients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS).ResultsThirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6–32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31–69%); DCR was 76% (95% CI: 59–88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients.All the cases showed expression of PDGFRβ in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRβ, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRβ immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%).ConclusionsSorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRβ-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.     

三氧化二砷对涎腺导管癌抑制作用的初步观察

目的观察三氧化二砷（As2O3）对人涎腺导管癌（Salivaryductcarcinoma）细胞的抑制作用,探索治疗人涎腺导管细胞癌的新途径。方法建立人涎腺导管癌细胞系,应用不同浓度As2O3在不同时间点作用人涎腺导管癌细胞株,以MTT和形态学分析法观察细胞的变化。结果不同浓度三氧化二砷在不同时间点对人涎腺导管癌细胞均有明娃抑制作用,并呈时间剂量依赖关系,癌细胞异形性逐渐消失,细胞凋亡现象明显,可见凋亡小体。结论As2O3对人涎腺导管癌细胞株具有显著的抑制增殖、诱导分化和促进凋亡作用。     

Report of a unique case of myoepithelial carcinoma of left parotid gland with metachronous bilateral cavernous sinus metastasis

Myoepithelial carcinoma (MC) is a rare, locally aggressive malignant neoplasm of the salivary glands. Only few evidences on its metastatic behavior are available in the literature. We herein present a unique case of MC of left parotid gland which metastasized to bilateral cavernous sinuses. The patient was successfully treated with palliative radiotherapy and chemotherapy.     

Salivary gland carcinoma treated with concomitant chemoradiation with intraarterial cisplatin and docetaxel

Malignant neoplasms of the salivary gland are uncommon entities in which surgical resection of the primary lesion has been accepted as a standard therapeutic option. The efficacy of radiation and systemic chemotherapy has been limited for patients with recurrent, metastatic, or unresectable disease because of unfavorable response rates and the short duration of the response. We treated one patient with recurrent adenoid cystic carcinoma arising from the sublingual gland and one patient with primary adenocarcinoma arising from the parotid gland with transfemoral intraarterial chemotherapy, based on full-dose cisplatin and docetaxel and concurrent external-beam radiotherapy. The doses of cisplatin and docetaxel in the two patients were 80–100 mg/m² and 10–15 mg/m², respectively. Docetaxel was infused first, followed by cisplatin. Both patients obtained complete responses. Although complications such as mucositis, anorexia, neutropenia, and ischemic colitis were observed, they were well tolerated and manageable. The concomitant chemoradiotherapy of cisplatin and docetaxel seemed to be a practicable option for patients with recurrent and unresectable salivary gland carcinomas.     

唾液腺显像对鼻咽癌放疗后腮腺功能的评价

目的探讨唾液腺显像对鼻咽癌放疗后腮腺功能的评价。方法对40例鼻咽癌行适形调强放疗（30例）及常规放疗（10例）的患者,分别于放疗前、放疗结束时及放疗后5个月作口干程度的比较及唾液腺功能显像榆查。结果放疗结束时患苦出现不同程度口干症状,放疗后5个月,部分患者口千症状有明显改善。唾液腺受损后腮腺显像图像征象及时问放射性曲线均有变化。放疗结束时腮腺定量分析摄取指数（UI）及分泌指数（E1）均比放疗前低（P〈0．05）,但适形调强放疗组的UI及EI均比常规放疗组高（P〈0．05）。结论适形凋强放疗可以有效保护腮腺功能,唾液腺显像可用于监测鼻咽癌放疗后腮腺功能变化。     

Mucoepidermoid carcinoma of salivary glands: A French Network of Rare Head and Neck Tumors (REFCOR) prospective study of 292 cases

BackgroundTo describe the characteristics of the largest European study of MEC of salivary glands and to determine the prognostic factors for overall and disease free survival.Patients and methodsPatients with MEC were prospectively included in the Réseau d’Expertise Français sur les Cancers ORL Rares (REFCOR, French Network of Rare Head and Neck Tumors) database between 2009 and 2015.ResultsA total of 292 patients were included. Tumors were classified as low grade in 175 cases (60%), intermediate in 39 (13%) and high grade in 78 (27%). Median follow-up was 26 months. The 5-year OS and DFS rates were respectively 83% and 69%. In multivariate analysis, age (p = 0.004), diabetes (p = 0.02) and advanced stage (p = 0.03) were found to have a significant negative impact on OS. Diabetes (p = 0.001), alcohol consumption (p = 0.003) and advanced stage (p = 0.001) were found to have a significant negative impact on DFS. Compare to low grade, high grade tended to have a negative impact on OS (p = 0.05) and had a significant effect on DFS (0.002) while intermediate grade had no significant influence on survival. The surgical treatment had a positive impact on both OS (p = 0.00005) and DFS (p = 0.0005). Postoperative radiotherapy had no impact in multivariate analysis.ConclusionAdvanced clinical stage, high grade tumor, high age, the impossibility of carrying out a complete surgical resection, and diabetes are the main prognostic factors in this prospective series of patients with MEC. Such findings open new research perspectives on the influence of these components on initial patient care.     

涎腺腺样囊性癌增殖、侵袭及转移相关信号通路的研究进展

涎腺腺样囊性癌是最常见的涎腺恶性肿瘤之一,其生长缓慢、侵袭性强,常沿骨膜和神经扩散,早期即可发生远处转移.涎腺腺样囊性的侵袭和转移是一个多阶段、多因素参与的过程,涉及复杂的机制和多条信号转导通路.文章就相关信号通路的研究进展进行综述.     

Pim-1 acts as an oncogene in human salivary gland adenoid cystic carcinoma

Background

Pim-1 (Provirus integration site for Moloney murine leukemia virus 1) belongs to the Ser/Thr kinase family and plays a pivotal role in occurrence and development of oncogenesis. Recent studies have demonstrated that Pim-1 phosphorylates RUNX3 and alters its subcellular localization. However, few studies have concerned the implications of Pim-1 in the salivary gland adenoid cystic carcinoma (ACC). In this study, we aimed to clarify the function of Pim-1 in ACC in vitro. Meanwhile, we measured the levels of Pim-1 and RUNX3 in the ACC tissues. The correlations between Pim-1/RUNX3 levels and clinical parameters were also analyzed.

Methods

SACC-83 and SACC-LM cells were transfected with the Pim-1 siRNA. Pim-1 mRNA and protein expression were measured using real-time PCR and immnuoblot, respectively. Cell proliferation was analyzed by CCK-8 assay. Cell cycle, apoptosis, and mitochondrial membrane potential were detected by flow cytometry. Effects of Pim-1 on cells’ invasion were evaluated by transwell migration assay. Pim-1 and RUNX3 levels in ACC tissues were examined by immunohistochemistry.

Results

Pim-1 siRNA reduces cell proliferation, induces apoptosis, causes cell cycle arrest through cell cycle related proteins (Cyclin D1 and CDK4), mitochondrial depolarization, and decreases invasive ability in SACC-83 and SACC-LM cells. Pim-1 and RUNX3 levels are significantly relevant and associated with T-stage and nerve invasion in the ACC tissues.

Conclusions

This study demonstrates the oncogenic role of Pim-1 in ACC. The findings also suggest that Pim-1 may serve as a neoteric therapeutic target and potential prognostic marker for ACC cancer.

     

Induction of Squamous Cell Carcinomas in the Salivary Glands of Rats by Potassium Iodide

In a 2-year carcinogenicity study of potassium iodide (KI) in F344/DuCrj rats, squamous cell carcinomas (SCCs) were observed in the salivary glands of 4/40 males and 3/40 females receiving 1000 ppm KI in the drinking water. Ductular proliferation with lobular atrophy was observed at high incidence in the submandibular glands of the high-dose animals, and squamous metaplasia was frequently evident within the proliferative ductules and the larger interlobular ducts. A transition from metaplasia to SCC was apparent. The results suggest that squamous metaplasia in proliferative ductules, occurring secondarily to lobular impairment induced by KI, may develop into SCCs via a non-genotoxic, proliferation-dependent mechanism.     

鼻中隔涎腺腺泡细胞癌1例

涎腺腺泡细胞癌是一种临床上少见的低度恶性肿瘤,多发生于腮腺、颌下腺、舌下腺及小唾液腺等涎腺。发生于鼻中隔的极为罕见,本文报道一例近期发现的位于鼻中隔的涎腺腺泡细胞癌。     

Expression of epidermal growth factor receptor in different salivary adenoid cystic carcinoma cell lines

Objective： To investigate the expression of epidermal growth factor receptor, a receptor tyrosine protein kinase, in the subcellular fractions of human salivary adenoid cystic carcinoma cell lines SACC-83 and SACC-LM. Methods： Low metastatic and high metastatic cells of the adenoid cystic carcinoma, SACC-83 and SACC-LM, were cultured. Their subcellular fractions were extracted. The expression of epidermal growth factor receptor was detected with Western blot method, and the results of protein expression were quantitatively analyzed by FluorChem V2.0 software. Results： The results of Western blot analysis indicated that, EGFR expression on the membrane of SACC-83 cells was significantly higher than that of SACC-LM cells, but its expression in cytoplasm was significantly less in the former than the later （P〈0.01）. In SACC-83 cell line, EGFR was over-expressed in membrane （P〈0.01）, but in SACC-LM cell line, EGFR was over-expressed in cytoplasm （P〈0.01）. Conclusion： The results suggest that the obtaining of metastasis ability is related to the high expression of EGFR protein in cytoplasm, so the molecular targeting therapy to EGFR may be an ideal treatment for the invasion and metastasis of salivary adenoid cystic carcinoma.     

涎腺导管癌的病理组织学特征分析

目的 探讨涎腺导管癌的病理特征、诊断及鉴别诊断.方法 回顾性分析涎腺导管癌的组织学及免疫组织化学特征.结果 大体检查:肿瘤为质硬灰白色边界不清肿块;光镜下肿瘤呈巢团状、腺样生长,瘤细胞较大,异型性明显.结论 涎腺导管癌是一类恶性程度很高的恶性肿瘤,主要依靠组织病理学及免疫组织化学检查结果确诊.     

层粘连蛋白与涎腺腺样囊性癌肿瘤生物学特性的关系研究

目的为研究层粘连蛋白与涎腺腺样囊性癌（ＡＣＣ）侵袭和转移的关系。方法用免疫组织化学ＡＢＣ法，观察２５例ＡＣＣ组织中层粘连蛋白（ＬＮ）的表达与分布。结果ＬＮ主要分布在基底膜上以及部分筛状假囊内，腺管内和肿瘤细胞浆内。经统计学检验，发现ＬＮ与病理分型、ＴＮＭ分期和转移有关，即筛状┐管状型、ＴＮＭ早期和无转移者的ＬＮ多阳性表达，而实体型、ＴＮＭ晚期和转移者，ＬＮ多阴性表达。结论ＬＮ表达的高低与ＡＣＣ临床恶性程度侵袭和转移，均有密切关系。     

鼻咽癌面颈联合野放疗对唾液腺功能的影响

为动态观察鼻咽癌病人行面颈联合野常规放疗前后唾液分泌量及有关成份浓度变化情况，分别对１８例病人于疗前、放疗１０Ｇｙ、２０Ｇｙ、３０Ｇｙ、４０Ｇｙ后取样。结果发现：①鼻咽癌患者放疗前无明显唾液腺功能障碍，随着放射剂量增加，分泌量逐渐减少，较面颈分野照射的病人症状发生程度无明显差异。②疗前患者唾液ｐＨ值正常，经照射后下降，并伴唾液Ｎ＋ａ浓度升高，Ｋ＋浓度下降。③唾液淀粉酶含量照射后较疗前要低。④唾液Ｃａ浓度疗后较疗前略升高