Salivary gland cancers are an incredibly heterogeneous group of tumors that include 24 histologically distinct tumor types. The use of new genetic methods has paved the way for promising advancements in our understanding of the molecular biology underlying each type of tumor. The objective of this review was to highlight common oncogenes, tumor suppressor genes, and cytogenetic and epigenetic changes associated with the most common tumor types: mucoepidermoid carcinoma, adenoid cystic carcinoma, salivary duct carcinoma, mammary analogue secretory carcinoma, hyalinizing clear cell carcinoma, carcinoma ex pleomorphic adenoma, and acinic cell carcinoma. Recent insights into the pathogenesis of each cancer subtype have helped better define and classify these tumors. Further research in salivary gland cancers should focus on determining the key genes involved in the tumorigenesis of each distinct malignancy and identifying individualized chemotherapies directed at these targets. Cancer 2016;122:1822-31. © 2016 American Cancer Society.

Local and systemic complications of Bacillus Calmette-Guérin therapy are important to recognize as they require prolonged antimicrobial therapy; molecular genomic testing may be key to diagnosis when culture data are inconclusive.

Human papillomavirus-related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is a relatively new clinical entity that is dramatically on the rise globally. HPV+ OPSCC is thought to be a separate clinical entity compared to HPV- OPSCC with a distinct tumor biology. Patients with HPV associated disease have been shown to have a substantially better prognosis and overall survival than those patients with the HPV negative (HPV-) counterpart. The standard of care for OPSCC is definitive radiation therapy (RT) and concurrent chemoradiation therapy (CRT), for lower and higher stage disease, respectively. However, traditional CRT is also associated with severe acute and late toxicities affecting patient quality of life, such as severe mucositis, dry mouth and dysphagia. Considering that HPV+ OPSCC is on the rise in a younger, healthier patient population and the good prognosis of HPV-related disease, there has been a focus on reducing treatment toxicities and optimizing quality of life while maintaining favorable oncologic outcomes. A variety of such de-escalation regimens are currently being explored in recently completed and ongoing clinical trials. Alterations to the standard chemotherapy, radiation and surgical regimens are being explored. This review will provide an overview of the rationale for and available results of the major de-intensification strategies in the treatment of locally advanced HPV+ OPSCC.

Epidermal growth factor receptor (EGFR) inhibitors are approved by the Food and Drug Administration (FDA) but remain under active clinical investigation for the treatment of both newly diagnosed and recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Despite EGFR expression in the majority of HNSCC tumors, the levels of total or phosphorylated EGFR have not consistently been correlated with a response to EGFR targeting agents. The lack of predictive biomarkers represents a major obstacle to successful use of these drugs. Activation of phosphatidylinositol 3-kinase (PI3K) signaling by mutation of the PIK3CA oncogene represents a plausible mechanism for EGFR inhibitor drug resistance. We compared the impact of EGFR inhibitors, alone or in combination with non-steroidal anti-inflammatory drugs (NSAIDs), in preclinical HNSCC models harboring mutant versus wild-type PIK3CA. Our results demonstrate additive or synergistic effects of NSAIDs and EGFR inhibitors in vitro and in vivo in PIK3CA-mutated HNSCC models. These findings suggest that the addition of NSAIDs to EGFR inhibitors for the treatment of HNSCC may represent a promising therapeutic strategy in PIK3CA-mutated cancers.

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

Purpose

Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. To explore the genetic origins of MEC, we performed systematic genomic analyses of these tumors.

Experimental design

Whole-exome sequencing and gene copy-number analyses were performed for 18 primary cancers with matched normal tissue. FISH was used to determine the presence or absence of the MECT1-MAML2 translocation in 17 tumors.

Results

TP53 was the most commonly mutated gene in MEC (28%), and mutations were found only in intermediate- and high-grade tumors. Tumors with TP53 mutations had more mutations overall than tumors without TP53 mutations (P = 0.006). POU6F2 was the second most frequently mutated gene, found in three low-grade MECs with the same in-frame deletion. Somatic alterations in IRAK1, MAP3K9, ITGAL, ERBB4, OTOGL, KMT2C, and OBSCN were identified in at least two of the 18 tumors sequenced. FISH analysis confirmed the presence of the MECT1-MAML2 translocation in 15 of 17 tumors (88%).

Conclusions

Through these integrated genomic analyses, MECT1-MAML2 translocation and somatic TP53 and POU6F2 mutations appear to be the main drivers of MEC. Clin Cancer Res; 23(1); 283-8. ©2016 AACR.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials.

Background

Papillary cystadenoma is a rare benign epithelial tumor of the salivary gland, which is characterized by papillary structures and oncocytic cells with rich eosinophilic cytoplasm. We found only one case of papillary cystadenoma in nearly 700 cases of salivary gland tumors. Our case was initially mistaken for a tumor of the right temporomandibular joint (TMJ) capsule rather than of parotid gland origin. Preoperative magnetic resonance imaging (MRI) and computed tomography (CT) should be carefully studied, which allows for appropriate preoperative counseling and operative planning.

Case summary

Here, we report an unusual case of a 54-year-old woman with a parotid gland papillary cystadenoma (PGPC) that was misdiagnosed as a tumor of the right TMJ capsule. She was initially admitted to our hospital due to a mass anterior to her right ear inadvertently found 5 d ago. Preoperative CT and MRI revealed a well circumscribed tumor that was attached to the right TMJ capsule. The patient underwent a resection through an incision for TMJ, but evaluation of an intraoperative frozen section revealed a benign tumor of the parotid gland. Then we removed part of the parotid gland above the temporal facial trunk. The facial nerve was preserved. Postoperative histopathological findings revealed that the tumor was PGPC. No additional treatment was performed. There was no recurrence during a 20-mo follow-up period.

Conclusion

The integrity of the interstitial space around the condyle in MRI or CT should be carefully evaluated for parotid gland or TMJ tumors.

Adenoid cystic carcinoma (ACC), the second most common salivary gland malignancy, is notorious for poor prognosis, which reflects the propensity of ACC to progress to clinically advanced metastatic disease. Due to high long-term mortality and lack of effective systemic treatment, the slow-growing but aggressive ACC poses a particular challenge in head and neck oncology. Despite the advancements in cancer genomics, up until recently relatively few genetic alterations critical to the ACC development have been recognized. Although the specific chromosomal translocations resulting in MYB-NFIB fusions provide insight into the ACC pathogenesis and represent attractive diagnostic and therapeutic targets, their clinical significance is unclear, and a substantial subset of ACCs do not harbor the MYB-NFIB translocation. Strategies based on detection of newly described genetic events (such as MYB activating super-enhancer translocations and alterations affecting another member of MYB transcription factor family-MYBL1) offer new hope for improved risk assessment, therapeutic intervention and tumor surveillance. However, the impact of these approaches is still limited by an incomplete understanding of the ACC biology, and the manner by which these alterations initiate and drive ACC remains to be delineated. This manuscript summarizes the current status of gene fusions and other driver genetic alterations in ACC pathogenesis and discusses new therapeutic strategies stemming from the current research.

The incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma continues to increase. Accurate diagnosis of the HPV status of a tumor is vital, as HPV+ versus HPV- tumors represent two unique biological and clinical entities with different treatment strategies. High-risk HPV subtypes encode oncoproteins E6 and E7 that disrupt cellular senescence and ultimately drive tumorigenesis. Current methods for detection of HPV take advantage of this established oncogenic pathway and detect HPV at various biological stages. This review article provides an overview of the existing technologies employed for the detection of HPV and their current or potential future role in management and prognostication.