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Background: There is no consensus about effective systemic therapy for salivary gland carcinomas (sgcs). Our aim was summarized the clinical trials assessing the systemic therapies (ST) on sgcs., Material and Methods: Electronic searches were carried out through MEDLINE/pubmed, EMBASE, Scopus, Web of Science, and the Cochrane Library databases, and gray literature., Results: Seventeen different drugs were evaluated, and the most frequent histological subtype was adenoid cystic carcinoma (n=195, 45.5%). Stable disease, observed in 11 ST, achieved the highest rate in adenoid cystic carcinoma treated with sunitinib. The highest complete (11.1%) and partial response (30.5%) rates were seen in androgen receptor-positive tumors treated with leuprorelin acetate., Conclusions: Despite all the advances in this field, there is yet no effective evidence-based regimen of ST, with all the clinical trials identified showing low rates of complete and partial responses. Further, translational studies are urgently required to characterize molecular targets and effective ST.

The aim of this study was to describe the prevalence, clinicopathological, and prognostic features of acinic cell carcinoma (AciCC) of the oral and maxillofacial region. AciCC cases were retrospectively retrieved from 11 pathology centers of three different countries. Medical records were examined to extract demographic, clinical, pathologic, and follow-up information. A total of 75 cases were included. Females (65.33%) with a mean age of 45.51 years were mostly affected. The lesions usually presented as an asymptomatic (64.28%) nodule (95.66%) in the parotid gland (70.68%). The association of two histopathological patterns was the most common finding (48.93%) and the tumors presented mainly conventional histopathological grades (86.11%). Surgical treatment was performed in the majority of the cases (59.19%). Local recurrence was observed in 20% of the informed cases, regional metastasis in 30.43%, and distant metastasis in 12.50%. The statistical analysis showed that the cases with a solid histopathological pattern (p=0.01), high-grade transformation (p=0.008), recurrence (p=0.007), and regional metastasis (p=0.03) were associated with poor survival. In conclusion, high histopathological transformation, presence of nodal metastasis, and recurrence were prognostic factors for AciCC of the oral and maxillofacial region.

Objective: Salivary gland tumors (SGT) are a diverse group of uncommon neoplasms that are rare in pediatric patients. This study aimed to characterize the clinicopathological profile of pediatric patients affected by SGT from a large case series derived from an international group of academic centers., Study Design: A retrospective analysis of pediatric patients with SGT (0-19 years old) diagnosed between 2000 and 2021 from Brazil, South Africa, and the United Kingdom was performed. SPSS Statistics for Windows was used for a quantitative analysis of the data, with a descriptive analysis of the clinicopathological characteristics and the association between clinical variables and diagnoses., Results: A total of 203 cases of epithelial SGT were included. Females were slightly more commonly (56.5%), with a mean age of 14.1 years. The palate was the most common site (43.5%), followed by the parotid gland (29%), lip (10%), and submandibular gland (7.5%). The predominant clinical presentation was a flesh-colored, smooth, and painless nodule. Pleomorphic adenoma (PA) was the most frequently diagnosed SGT (58.6%), followed by mucoepidermoid carcinoma (MEC) (26.6%). Surgery (90.8%) was the favored treatment option., Conclusions: Benign SGT in pediatric patients are more commonly benign than malignant tumors. Clinicians should keep PA and MEC in mind when assessing nodular lesions of possible salivary gland origin in pediatric patients., Competing Interests: Declaration of competing interest The authors declare no conflict of interest or any commercial associations., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Adenoid cystic carcinoma (ACC) has a significant patient-population in need of effective systemic therapy, as no drug is currently approved by the FDA for its management. We critically reviewed ACC-clinical trials (CT) registered on the ClinicalTrials.gov website using "ACC" under condition or disease. Trials specifically designed to test a drug-based therapy for ACC (n = 33) were analyzed with most being one-arm phase II trials enrolling advanced, recurrent/metastatic, incurable ACC cases. Site restriction, maximum ECOG status, and period of disease progression varied as inclusion criteria. Small-molecule inhibitors were those most commonly investigated with Apatinib, Axitinib and Lenvatinib showing the best results in association with rigid enrollment criteria. The overall median time to progression remains modest and more efforts are urgently needed in this field. CTs designed to test drugs that act on key pathways associated with ACC aggressiveness are being conducted and represent a promising pathway if efficacy is proved., Competing Interests: Conflict of Interest The authors declare no competing interests. The funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Appropriate DNA replication is vital to maintain cell integrity at the genomic level. Malfunction on DNA repair mechanisms can have implications related to tumor behavior. Our aim was to evaluate the expression of key complexes of the DNA mismatch-repair system MutSα (hMSH2-hMSH6) and MutSβ (hMSH2-hMSH3) in a panel comprising the most common benign and malignant salivary gland tumors (SGT), and to determine their association with disease-free survival., Material and Methods: Ten cases of normal salivary gland (NSG) and 92 of SGT (54 benign and 38 malignant) were retrieved. Immunohistochemistry was performed for hMSH2, hMSH3, hMSH6. Scanned slides were digitally analyzed based on the percentage of positive cells with nuclear staining. Cases were further classified in MutSαhigh and MutSβhigh based on hMSH2-hMSH6 and hMSH3-hMSH6 expression, respectively., Results: hMSH3 expression was lower in malignant SGT compared to NSG and benign cases. Adenoid cystic carcinoma (ACC) cases with perineural invasion presented a lower percentage of hMSH3 positive cells. hMSH6 was downregulated in both benign and malignant SGT compared to NSG. Malignant SGT cases with MutSαhigh expression had lower disease-free survival compared to MutSαlow cases. A 10.26-fold increased risk of presenting local recurrence was observed., Conclusions: Our findings suggest that a lack of hMSH3 protein function is associated with a more aggressive phenotype (malignancy and perineural invasion) and that MutSα overexpression predicts a poor clinical outcome in malignant SGT.

Background: The aim of the present systematic review was to analyze the available data regarding acinic cell carcinoma of the oral and maxillofacial region., Methods: A search strategy was performed using PubMed, Web of Science, Scopus, and Embase electronic databases., Results: Available data revealed a slight female preference (54.73%) and a mean age at diagnosis of 47.51 ± 19.85 years. The parotid glands (67.72%) were most frequently affected, and most cases were asymptomatic (69.54%). A microcystic histopathological pattern was reported in 21.56% of the cases, and the Periodic acid-Schiff was the staining method most frequently used, after the hematoxylin and eosin staining, in the tumors analyzed. The lesions were mainly treated by surgical removal (72.32%). Recurrence was reported in 81 cases (27.83%) and metastasis in 100 (42.91%). Statistical data analysis revealed that tumors located in major salivary glands and exhibiting high-grade histology were associated with local recurrence (P = .01). In addition, the patients older than 57 years, lesions with bone involvement, the high-grade tumors and the cases with a history of recurrence and metastasis were associated with a lower overall survival (P < .05)., Conclusion: By assembling all eligible cases in the literature, the present systematic review determined the most common clinicopathological profile of acinic cell carcinoma and the most relevant prognostic factors in a distinctly representative sample. The survey demonstrated the importance of considering the histopathological grading in order to better define the treatment for each case., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The aim of this study was to identify tumor parenchyma cells exhibiting immunohistochemical profile of stem cells by evaluating the immunoreactivity of OCT4 and CD44 in a number of cases of salivary gland neoplasms. The sample consisted of 20 pleomorphic adenomas, 20 mucoepidermoid carcinomas, and 20 adenoid cystic carcinomas located in major and minor salivary glands. The expression of OCT4 and CD44 was evaluated by the percentage of positive cells and the intensity of expression. All studied cases showed positive expression of OCT4 and CD44 and higher values than the control groups. For OCT4, luminal and non-luminal cells were immunostained in the case of pleomorphic adenomas and adenoid cystic carcinomas. Moreover, the immunoreactivity of CD44 was particularly evident in the non-luminal cells of these lesions. In mucoepidermoid carcinomas, there was immunoreactivity for both markers in squamous and intermediate cells and absence of staining in mucous cells. For both markers, a significantly higher immunostaining was verified in neoplasms located in the major salivary glands compared with lesions in minor salivary glands (p<0.001). In the total sample and in minor salivary glands, malignant neoplasms exhibited higher immunoreactivity for OCT4 than pleomorphic adenoma. A significant moderate positive correlation (r = 0.444 and p ≤ 0.001) was found between OCT4 and CD44 immunoexpression in the total sample. The high expression of OCT4 and CD44 may indicate that these proteins play an important role in identifying tumor stem cells.

Background: Salivary gland cancers (SGC) represent an uncommon group of heterogeneous tumors. We performed a retrospective survey of SGC diagnosed in a reference center for treatment of malignant tumors from the south of Brazil aiming to determine the prognostic value of demographic, clinic and pathologic features., Material and Methods: Cases diagnosed as SGC between 2006 and 2016 were retrospectively collected. Medical records were examined to extract demographic, clinic, pathologic and follow-up information., Results: One-hundred and seven cases of SGC were identified. The most common SGC were mucoepidermoid carcinoma (MEC) (n = 39) followed by adenoid cystic carcinoma (AdCC) (n = 29). Among AdCCs, 55.2% of cases were classified as cribriform, 27.6% as tubular and 17.2% as solid. The tubular subtype had the highest percentage of cases with perineural invasion (p=0.01). Among MEC, 61.5% of cases were classified as low grade, 15.4% as intermediate grade and 19.9% as high grade. Low grade MEC had the lowest percentage of cases with perineural invasion (p=0.04). The 5-year survival for loco-regional control, disease-free survival (DFS) and disease-specific survival were 75%, 70% and 84%, respectively. The following features were associated with poor DFS: advanced age (p=0.03), rural residency (p=0.01), being a smoker or former smoker (p=0.01), pain (p=0.03), nodal metastasis (p<0.001), need for chemotherapy (p=0.02), neck dissection (p=0.04), perineural invasion (p=0.01), and being diagnosed with AdCC compared to MEC (p=0.02)., Conclusions: The clinco-demographic and pathologic features identified as prognostic factors reveal the profile of patients at increased risk of recurrence and who would benefit from closer follow-up.

Background: Salivary gland tumors are a diverse group of uncommon neoplasms that are rare in pediatric patients. The aim of this study was to evaluate the clinicopathological profile and survival outcomes of pediatric patients affected by salivary gland tumors., Materials and Methods: An extensive search was carried out using the MEDLINE/PubMed, EMBASE, Scopus databases, and grey literature. The risk of bias was available in all papers included., Results: A total of 2,830 articles were initially retrieved with 54 remaining for data extraction, resulting in 2,937 cases. This comprised forty-five case series' and nine cohort studies. These tumors were slightly more prevalent in females (57.4%). The patients' age ranged from 0.3 to 19 years old, with a mean age of 13.3 years. Parotid was the most affected site (81.9%), and 99.2% of cases clinically exhibited a swelling. Presence of pain/tenderness was reported in 13.5% of the cases, with an average duration of 12.6 months for the appearance of symptoms. Most of the reported cases were malignant tumors (75.4%), with mucoepidermoid carcinoma the most common tumor of all tumors (44.8%), followed by pleomorphic adenoma (24.1%). Surgery alone was the leading treatment choice in 74.9% cases, and the 5-year overall survival rate of patients was 93.1%. Patients with symptoms (P = .001), local recurrence (P < .001), metastasis (P < .001), and those not undergoing surgery or surgery combined with radiotherapy (P < .001) showed lower survival rates., Conclusion: The pediatric patients present a high frequency of malignant salivary neoplasms and a high overall survival rate., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The presence of the CRTC1-MAML2 translocation has been described in mucoepidermoid carcinoma (MEC) as a predictor of better survival rates. However, the real prognostic value of the translocation has been debated due to recent controversial findings. The aim of this study was to perform a systematic review to understand the prognostic potential of the CRTC1-MAML2 translocation in MEC. An electronic search was carried out using the MEDLINE/PubMed, EMBASE and Scopus databases. Articles that assessed the association between the CRTC1-MAML2 translocation and survival of MEC patients were selected for the systematic review. Ten published articles were included in the qualitative synthesis. The prevalence of the translocation varied from 33.7% to 69.7%. Seven studies observed a significant association between the presence of the CRTC1-MAML2 translocation and a favourable clinical outcome, which could improve disease-free, disease-specific or overall survival. Five studies were included in the quantitative synthesis. Fixed-effects model confirmed that translocation-positive patients have a decreased risk of death (combined odds ratio 0.08, 95% confidence interval - 0.03-0.23, P < .00001). The detection of the CRTC1-MAML2 translocation appears to be useful as a prognostic factor in MEC. However, the level of evidence is not as high as it could be once important limitations were found in the published studies., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: The aim of this study was to determine the proteome of adenoid cystic carcinoma (AdCC) and polymorphous adenocarcinoma (PAc) and to identify a protein signature useful in distinguishing these two neoplasms., Study Design: Ten cases of AdCC and 10 cases of PAc were microdissected for enrichment of neoplastic tissue. The samples were submitted to liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the proteomics data were analyzed by using the MaxQuant software. LC-MS/MS spectra were searched against the Human UniProt database, and statistical analyses were performed with Perseus software. Bioinformatic analyses were performed by using discovery-based proteomic data on both tumors., Results: LC-MS/MS analysis identified 1957 proteins. The tumors shared 1590 proteins, and 261 were exclusively identified in AdCC and 106 in PAc. Clustering analysis of the statistically significant proteins clearly separated AdCC from PAc. Protein expression 10 times higher in one group than in the other led to a signature of 16 proteins-6 upregulated in AdCC and 10 in PAc. A new clustering analysis showed reverse regulation and also differentiated both tumors., Conclusions: Global proteomics may be useful in discriminating these two malignant salivary neoplasms that frequently show clinical and microscopic overlaps, but additional validation studies are still necessary to determine the diagnostic potential of the protein signature obtained., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mammaglobin is expressed in breast and salivary gland secretory carcinomas; however, its expression in salivary duct carcinomas (SDCs) still not well established. Therefore, the aim of this study was to investigate the presence and distribution of mammaglobin immunoexpression in SDC ex-PA in different phases of the adenoma to carcinoma sequence evaluating its possible involvement in carcinogenesis and tumor progression, as well as to determine its expression in SDC de novo. Mammaglobin immunohistochemistry was performed in 84 SG tumors, including 41 pleomorphic adenomas (PA) without malignant transformation, 13 intracapsular SDC ex-PA, 5 frankly invasive SDC ex-PA, 25 SDC de novo and 10 secretory carcinomas. The reactions were qualitatively analyzed and digitally scored. Positive immunostaining for mammaglobin was observed in 37 out of 84 SG tumors evaluated (44.1%), but strong staining was consistently seen only in secretory carcinomas, SDC de novo and frankly invasive SDC ex-PA, while it was weaker in intracapsular SDC ex-PA and PA. In PA, mammaglobin expression was significantly associated with recurrence. This study has confirmed that the mammaglobin is commonly expressed in SDC de novo and secretory carcinomas. Its expression was higher in SDC ex-PA than in PA, suggesting that mammaglobin may play a role in its malignant transformation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Malignancies from the salivary glands are rare and represent 11% of all cancers from the oropharyngeal anatomical area. Mucoepidermoid Carcinomas (MEC) is the most common malignancy from the salivary glands. Low survival rates of high-grade Mucoepidermoid Carcinomas (MEC) are particularly associated with the presence of positive lymph nodes, extracapsular lymph node spread, and perineural invasion. Most recently, the presence of cancer stem cells (CSC), and the activation of the NFκB signaling pathway have been suggested as cues for an acquired resistance phenotype. We have previously shown that NFκB signaling is very active in MEC tumors. Herein, we explore the efficacy of NFκB inhibition in combination with class I and II HDAC inhibitor to deplete the population of CSC and to destroy MEC tumor cells. Our finding suggests that disruption of NFκB signaling along with the administration of HDAC inhibitors constitute an effective strategy to manage MEC tumors.

Background: Epigenetic changes refer to any heritable modification in gene expression independent of alterations in the DNA sequence. Currently, it is well established that epigenetics represents a crucial player for tumor development. Nevertheless, the epigenetic mechanisms involved in the development and progression of salivary gland tumors (SGTs) remain poorly understood., Methods: In this study, we analyzed the pattern of acetyl-histone H3 (lys9) expression in benign and malignant SGTs and further correlate our results with tumors' proliferative activity and clinical outcomes. We assembled tissue microarrays (TMAs) of 84 cases of SGTs and analyzed for acetyl-histone H3 (lys9) and Ki-67 using immunohistochemistry. The study comprised 42 benign and 42 malignant SGTs., Results: All cases included in this study were positive to acetyl-H3 (lys9). We observed that malignant SGTs were hypoacetylated compared with benign (P = 0.04). Moreover, acetyl-H3 (lys9) expression was inversely correlated with Ki67 (**P = 0.02)., Conclusion: This study provides the first insight regarding histone modifications in SGTs. Our results suggest that epigenetic mechanism, particularly hypoacetylation of histone H3 (lys9), might play a role in the behavior of salivary gland tumors. Also, our findings suggest that interfering with the acetylation pattern of tumor histones represents a potential novel therapeutic strategy for the treatment of SGTs., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Pleomorphic adenoma (PA) is the most frequent benign epithelial lesion of salivary gland origin, showing great histopathological diversity. The aim of this study was to perform a retrospective analysis, with emphasis on histopathologic features of PA of salivary glands. Clinical and histopathologic characteristics of 130 cases of minor and major salivary glands PAs from three Brazilian reference centers were studied. Higher frequency of PAs was observed in female (55.4 %) subjects, with mean age of 49.7 years. The most common affected site was palate (64.5 %) for the PAs of minor salivary glands and parotid for cases affecting major glands (86.2 %). Microscopically, most cases were classified as classic PAs (50 %). Incomplete capsule was observed in 36.2 % of the cases, while 47.2 % showed capsular infiltration. Rounded (66.9 %), angular (49.2 %), oval (46.2 %) and plasmacytoid (39.2 %) cells were widely observed, as well as fibrous (73.8 %) and myxoid (69.2 %) stroma, squamous metaplasia (25.4 %) and cystic degeneration (43.1 %). Crystalloids (3.1 %), increased mitotic activity (5.4 %) and vascular invasion (2.3 %) were rarely observed. PAs arising in minor salivary glands were associated with incomplete capsules, spindle, oval, angular, plasmacytoid and pleomorphic cells, fibrous and hyaline stroma, cystic degeneration, squamous metaplasia and pleomorphism (p < 0.05). No association between capsular features and histological subtype was noted (p ≥ 0.05). These results confirm the findings of previous studies regarding major clinicopathological features of pleomorphic adenomas; and highlighted some important morphologic characteristics like the capsule, vascular invasion, pleomorphism and increased mitotic activity, which can reflect the biological behavior of these tumors.

Background: Salivary gland carcinomas are uncommon neoplasms and the identification of new prognostic indicators could improve their management. HOXB7 and HOXB9 are members of the class I homeobox-containing genes important for normal embryogenesis and that are dysregulated in several human neoplasms. This study investigated HOXB7 and HOXB9 expressions in salivary gland tumourigenesis, their correlation with neoplastic proliferative and angiogenic features and their importance as prognostic markers., Methods: A hundred and fifty salivary gland tumours were organized in tissue microarray and expressions of CD105, Ki67, HOXB7 and HOXB9 were determined through immunohistochemistry. Reactions were quantified and correlated with clinicopathological parameters., Results: In normal glands, HOXB7 was found in basal cells, whereas HOXB9 was seen in serous acinar and scattered ductal cells. Malignancies exhibited an increased vascular density, proliferative index, HOXB7 and HOXB9 expressions when compared with pleomorphic adenoma and Warthin's tumour. Significant correlation was found between HOXB7 and CD105 (P = 0.004) in adenoid cystic carcinomas, and HOXB7 higher expression significantly correlated with the presence of paresthesia (P = 0.02). No marker exhibited a significant association with survival rates (P > 0.05)., Conclusion: HOXB7 and HOXB9 were expressed in normal salivary gland and were present in benign and malignant tumours derived from these structures, and HOXB7 significantly correlated with neoangiogenesis in AdCC. These findings suggest that both proteins might play a role in salivary gland tumourigenesis, but they were not significant prognostic determinants in this sample., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mucoepidermoid carcinoma (MEC) is the most common malignancy of salivary glands. The response of MEC to chemotherapy is unpredictable, and recent advances in cancer biology suggest the involvement of cancer stem cells (CSCs) in tumor progression and chemoresistance and radioresistance phenotype. We found that histone acetyltransferase inhibitors (HDACi) were capable of disrupting CSCs in MEC. Furthermore, administration of HDACi prior to Cisplatin (two-hit approach) disrupts CSCs and sensitizes tumor cells to Cisplatin. Our findings corroborate to emerging evidence that CSCs play a key role in tumor resistance to chemotherapy, and highlights a pharmacological two-hit approach that disrupts tumor resistance to conventional therapy., Competing Interests: The authors declare no conflicts of interest.

Patient-derived xenograft (PDX) models are frequently used for translational cancer research, and are assumed to behave consistently as the tumor ages. However, growth rate constancy as a function of time is unclear. Notably, variable PDX growth rates over time might have implications for the interpretation of translational studies. We characterized four PDX models through several in vivo passages from primary human head and neck squamous cell carcinoma and salivary gland adenoid cystic carcinoma. We developed a mathematical approach to merge growth data from different passages into a single measure of relative tumor volume normalized to study initiation size. We analyzed log-relative tumor volume increase with linear mixed effect models. Two oral pathologists analyzed the PDX tissues to determine if histopathological feature changes occurred over in vivo passages. Tumor growth rate increased over time. This was determined by repeated measures linear regression statistical analysis in four different PDX models. A quadratic statistical model for the temporal effect predicted the log-relative tumor volume significantly better than a linear time effect model. We found a significant correlation between passage number and histopathological features of higher tumor grade. Our mathematical treatment of PDX data allows statistical analysis of tumor growth data over long periods of time, including over multiple passages. Non-linear tumor growth in our regression models revealed the exponential growth rate increased over time. The dynamic tumor growth rates correlated with quantifiable histopathological changes that related to passage number in multiple types of cancer.

Background: Salivary gland tumors (SGT) account for 3-10% of all head and neck neoplasms, and little is known about their angiogenic properties. Despite semaphorins and neuropilins have been demonstrated to be prognostic determinants in many human cancers, they remain to be investigated in SGT. Therefore, the objective of this study was to analyze the clinical significance of the expression of class 3 semaphorins A (Sema3A) and B (Sema3B) and neuropilins-1 (Np-1) and neuropilins-2 (Np-2), in SGT., Methods: Two hundred and forty-eight SGT were organized in tissue microarray paraffin blocks and expression of CD34, Sema3A, Sema3B, Np-1, and Np-2 was determined through immunohistochemistry. The immunoreactions were quantified using digital algorithms and the results correlated with clinicopathological parameters., Results: Malignant tumors had an increased vascular density than their benign counterparts and their increased vascular area significantly correlated with recurrences (P < 0.05). Patients older than 40 years and the presence of recurrences determined an inferior survival rate (P = 0.0057 and P = 0.0303, respectively). In normal salivary glands, Np-1 and Np-2 expression was restricted to ductal cells, whereas Sema3A and Sema3B were positive in the serous acinar compartment. Tumors were positive for all markers and the co-expression of Np-1/Np-2 significantly correlated with the presence of paresthesia and advanced stages of the tumors (P = 0.01 and P = 0.04, respectively)., Conclusion: Sema3A, Sema3B, Np-1, and Np-2 may be involved in the pathogenesis of SGT, but their expression did not present a statistically significant prognostic potential in this study., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Salivary gland tumors (SGT) are rare neoplasms that generate interest due to their histopathological diversity and clinical behavior. The aims of the present study were to investigate clinicopathological aspects of SGTs diagnosed at a tertiary health center and compare the findings with epidemiological data from different geographic locations. Cases of tumor in the head and neck region at a single health center in the period between 1995 and 2010 were reviewed. Patient gender, age and ethnic group as well as anatomic location, histological type and clinical behavior of the tumor were recorded. Availability of complete information about these aspects was considered the inclusion criteria. Descriptive statistical analysis of the data was performed using the frequencies of categorical variables. Among the 2168 cases of tumors in the head and neck region, 243 (11.20%) cases were diagnosed in the salivary glands, 109 of which met the inclusion criteria: 85 (78%) benign tumors and 24 (22%) malignant tumors. Mean patient age was 46.47 years. The female gender accounted for 56 cases (51.4%) and the male gender accounted for 53 (48.3%). The major salivary glands were affected more (75.2%) than the minor glands. The most frequent benign and malignant SGTs were pleomorphic adenoma (81.2%) and adenoid cystic carcinoma (58.3%), respectively. In conclusion, pleomorphic adenoma and adenoid cystic carcinoma are the most frequent benign and malignant lesions, respectively. Comparing the present data with previous studies on SGTs, one may infer that some demographic characteristics and the predominance of malignant tumors vary in different geographic regions.

Objective: The aim of this study was to analyze the expression pattern of proteins in the HGF/c-MET/PI3K signaling pathway in salivary gland tumors (SGTs) and to correlate the findings with the proliferative index and clinical parameters., Study Design: We assembled tissue microarrays (TMAs) of 108 cases of SGTs, including 69 cases of pleomorphic adenoma (PA), 24 cases of adenoid cystic carcinoma (AdCC), and 15 cases of mucoepidermoid carcinoma (MEC). An immunohistochemical analysis of hepatocyte growth factor (HGF), MET phosphorylation (p-MET), protein kinase B (AKT) phosphorylation (p-AKT), and Ki-67 proteins was performed., Results: Benign and malignant SGTs presented similar scores of HGF-positive cells (P = .36), whereas, malignant SGTs exhibited higher levels of p-MET (P = .001) and p-AKT (P = .001) than benign SGTs. No correlation of HGF, p-MET, or p-AKT expression was observed with clinical parameters. PA had a lower proliferative index than either AdCC (P = .001) or MEC (P = .001)., Conclusions: The salivary gland carcinomas exhibited increased activation of the HGF pathway, as evidenced by the phosphorylation of the MET receptor, and increased activation of the PI3K pathway, as indicated by p-AKT. These data suggest that the HGF/c-MET/PI3K signaling pathway is active in SGTs, especially in malignant neoplasms., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Salivary gland tumors (SGTs) consist of a heterogeneous group of lesions accounting for 3% to 10% of all head and neck neoplasms. Little is known about their angiogenic properties, and despite vascular endothelial growth factor (VEGF) has been previously studied in these lesions, further investigations are warranted to better determine its clinical and prognostic significance. In the current study, a total of 132 formalin-fixed, paraffin-embedded SGTs were organized in tissue microarray blocks and submitted to immunohistochemistry against VEGF protein. Slides were scanned and immunoreactions analyzed using Pixelcount V9 algorithm (Aperio Technologies Inc, Vista, CA, USA). Clinical and follow-up data were retrieved from patients' medical charts. Tumors included 50 cases of pleomorphic adenoma, 32 mucoepidermoid carcinomas, 30 adenocarcinomas not otherwise specified, and 20 adenoid cystic carcinomas. A slight male preponderance was found (1.1:1.0), with a mean age of 47.5 years. Parotid gland was the most affected location. Vascular endothelial growth factor expression was found in the cytoplasm of all cases analyzed with variable intensity, proving to be overexpressed in malignant tumors if compared with pleomorphic adenoma. A significant correlation of VEGF reactivity was found only with age, showing no further significant associations. Age and presence of paresthesia were the only features that predicted a lower specific survival rate under univariate and multivariate analyses. Log-rank test evidenced VEGF high expression as a potential determinant of reduced survival, although a statistical significance could not be reached. Hence, considering VEGF overexpression in malignant tumors and its potential association with a lower survival rate, this protein might be associated with SGTs pathogenesis and aggressiveness., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Adenoid cystic carcinoma (ACC) is a frequent malignant salivary gland neoplasm presenting different growth patterns described as tubular, cribriform and solid, which represent distinct differentiation stages. Cell lines originated from ACCs grown inside three-dimensional environments have not been capable to reproduce all in vivo ACC growth patterns. As ACC cells in vivo present replicated basement membrane, to mimic this situation in vitro ACC cells (CAC2 cells) were grown on the top of a reconstituted basement membrane (Matrigel). Phenotype differences were assessed by light, fluorescence and transmission electron microscopy. The cultures grown on the top of Matrigel presented three-dimensional arrangement of cells intercepted by cellular cords. At these, cell nests pseudocyst formations were observed. This morphological structure entirely reproduced the cribriform growth pattern of ACC. We suggest that the cribriform differentiation of ACC in culture is dependent of proteins and growth factors associated in a bi-dimensional structure.

Background: Epithelial-mesenchymal interactions constitute fundamental phenomena in the development and maintenance of the characteristic branching pattern seen in salivary glands. This study was undertaken to discuss the extracellular matrix (ECM) role in morphogenesis and cellular differentiation of salivary gland tumors originating from the intercalated duct., Methods: The ECM components, laminin (LN), type IV collagen, fibronectin (FN), and tenascin (TN) were revealed using a streptoavidin-biotin immunohistochemical technique and analyzed in 34 cases of salivary gland tumors: pleomorphic adenoma (PA); myoepithelioma; basal cell adenoma (BCA); polymorphous low grade adenocarcinoma (PLGA); and adenoid cystic carcinoma (ACC)., Results: LN and type IV collagen were present in all tumors, confining well-organized duct-like structures, separating them from the stroma, or surrounding cell clusters. In PA and myoepithelioma, the basement membrane (BM) fragmentation was observed through LN and type IV collagen staining around each individual spindle-shaped cell, which was strictly related to the cell modification. Interestingly, BM interruption could not be seen in the malign tumors, however, was frequently augmented in some cases. LN, type IV collagen, and FN were also found in the stroma of all tumors studied, except for the pseudocystic spaces of ACC, which were only delimited by replicated LN and type IV collagen. TN exhibited a variable expression, being more intense in solid ACC., Conclusions: LN and type IV collagen were always present around morphologically well-differentiated duct-like structures in all tumors studied. BM interruption could not be seen in the malign tumors, on the contrary BM production was evident, which is probably related to invasion. FN was present in the stroma of all tumors, but TN was mostly observed in less differentiated and higher degree of malignancy tumors, such as solid ACC.