Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy.

BACKGROUND: Patients with advanced primary and recurrent salivary duct carcinoma (SDC), a rare and lethal malignancy, have limited therapeutic options. Novel small-molecule agents aimed at targeting critical signaling associated with SDC tumorigenesis may lead to new therapeutic options for patients with these tumors. The human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3-kinase (PI3K) axis, an important oncogenic pathway, has been targeted for therapy in several solid tumors. Currently, little is known about the role and clinical implications of alterations of the HER2/PI3K pathway in patients with SDC. METHODS: The authors investigated the clinicopathologic features, genetic alterations, and expression of key members of the HER2/PI3K pathway in 43 primary tumors and conducted in vitro functional and targeted drug-response analyses on cell lines derived from salivary epithelial carcinomas. RESULTS: In primary tumors, loss of phosphatase and tensin homolog (PTEN) expression was identified in 22 of 43 tumors (51%), overexpression of HER2 was observed in 12 of 43 tumors (28%), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations were identified in 12 of 43 tumors (28%). Phosphorylated protein kinase B (p-AKT) was highly expressed in most tumors. Most tumors (70%) displayed mutually exclusive alterations of PI3K members, whereas 8 tumors (19%) had 2 or more concurrent abnormalities. In vitro studies demonstrated a direct association between PTEN loss and PI3K pathway activation and evidence of response to combined PI3Kα and PI3Kß and/or pan-PI3K inhibitors. CONCLUSIONS: The current analyses reveal frequent PTEN loss and mutually exclusive alterations of key PI3K pathway members in SDC and demonstrate in vitro evidence of a response to pan-PI3K inhibitors. These results provide a framework for a biomarker-based substratification of patients with SDC in future targeted therapy. Cancer 2018;124:3523-32. © 2018 American Cancer Society.

Frequent and differential mutations of the CYLD gene in basal cell salivary neoplasms: linkage to tumor development and progression.

Basal cell salivary neoplasms display similar cyto-morphologic features and are classified into adenoma and adenocarcinoma based on the presence or absence of tumor invasion at diagnosis. These neoplasms also share considerable phenotypic resemblance and co-exist with certain dermal adnexal tumors harboring the CYLD gene mutations inferring common genetic association. We sequenced the CYLD gene in both basal cell adenomas and adenocarcinomas and correlated the findings with CYLD, NF-κB, and ß-catenin expression levels and clinicopathologic factors. Twenty mutations were identified and comprised of 3 synonymous and 17 non-synonymous (missense) types involving the coding exons of the CYLD gene. Mutations in exons 9-11 were identified in both adenomas and adenocarcinomas, while mutations in exons 12-20, encoding the USP domain, were exclusively found in carcinomas. Although no significant correlation between CYLD mutations and expression levels of CYLD, NF-κB, and ß-catenin or clinicopathologic parameters was found, basal cell adenocarcinomas with multiple mutations showed reduction in CYLD protein expression and pursued aggressive clinical behavior. Our study revealed high incidence and sequential CYLD mutations in both basal cell adenoma and adenocarcinoma supporting a single neoplastic continuum for their evolution and provides evidence for potential diagnostic and therapeutic utility.

Mohs moat: peripheral cutaneous margin clearance in a collaborative approach for aggressive and deeply invasive basal cell carcinoma.

Although Mohs micrographic surgery is the standard of care for large, aggressive or recurrent non-melanoma skin cancers of the head and neck, tumours that involve deep underlying structures (including bone, parotid gland and named nerves) are impractical for extirpation under local anaesthesia. Such cases are often referred to a head and neck surgeon, who typically relies on intraoperative frozen section analysis of the peripheral cutaneous margin. Here we describe the use of the Mohs moat technique as part of a collaborative approach for the treatment of aggressive and deeply invasive basal cell carcinoma that allows an analysis of the complete peripheral cutaneous margin and results in decreased operating room and general anaesthesia time.

A prototype tobacco-associated oral squamous cell carcinoma classifier using RNA from brush cytology.

BACKGROUND: Oral cancer in the form of squamous cell carcinoma (OSCC) is typically detected in advanced stages when treatment is complex and may not be curative. The need for surgical biopsy may contribute to delays in diagnosis and impede early detection. Multiple studies of RNA from surgically obtained tumor samples have revealed many genes differentially expressed with this disease. We sought to determine whether the identified mRNAs could be used as markers by a non-invasive detection system for OSCC using RNA from brush cytology. METHODS: Levels of mRNAs from 21 genes known to be differentially expressed in head and neck squamous cell carcinoma surgical samples, compared with controls, were shown to be quantifiable in oral brush cytology samples. These mRNAs were quantified in a training set of 14 tumor and 20 non-malignant brush cytology samples from tobacco/betel nut users. With the measurement of two additional mRNAs and analysis using support vector machines algorithm for class prediction of these cancers was produced. RESULTS: This OSCC classifier based on the levels of 5 mRNAs in RNA from brush cytology initially showed 0.93 sensitivity and 0.91 specificity in differentiating OSCC from benign oral mucosal lesions based on leave-one-out cross-validation. When used on a test set of 19 samples from 6 OSCCs and 13 non-malignant oral lesions, we found misclassification of only one OSCC and one benign lesion. CONCLUSIONS: This shows the promise of using RNA from brush cytology for early OSCC detection and the potential for clinical usage of this non-invasive classifier.

Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations.

PURPOSE: Salivary gland carcinomas (SGCs) are pathologically classified into several widely diverse subtypes, of which adenoid cystic carcinoma (ACC), mucoepidermoid carcinoma (MEC), and salivary duct carcinoma (SDC) are the most commonly encountered. A comparative genetic analysis of these subtypes provides detailed information on the genetic alterations that are associated with their tumorigenesis and may lead to the identification of biomarkers to guide tumor-specific clinical trials. EXPERIMENTAL DESIGN: Whole-genome sequencing of 58 common SGCs (20 ACCs, 20 SDCs, and 18 MECs) was performed to catalog structural variations, copy number, rearrangements, and driver mutations. Data were bioinformatically analyzed and correlated with clinicopathologic parameters, and selected targets were validated. RESULTS: Novel and recurrent type-specific and shared genetic alterations were identified within and among 3 subtypes. Mutually exclusive canonical fusion and nonfusion genomic alterations were identified in both ACC and MEC. In ACCs, loss of chromosome 12q was dominant in MYB or MYBL1 fusion-positive tumors and mutations of NOTCH pathway were more common in these fusion negatives. In MECs, CRTC1-MAML2 fusion-positive tumors showed frequent BAP1 mutation, and tumors lacking this fusion were enriched with LRFN1 mutation. SDCs displayed considerable genetic instability, lacked recurrent chromosomal rearrangements, and demonstrated nonoverlapping TP53 mutation and ERBB2 amplification in a subset of tumors. Limited genetic alterations, including focal amplifications of 8q21-q23, were shared by all subtypes and were associated with poor survival. CONCLUSIONS: This study delineates type-specific and shared genetic alterations that are associated with early phenotypic commitment and the biologic progression of common SGCs. These alterations, upon validation, could serve as biomarkers in tumor-specific clinical trials.

Reciprocal and Autonomous Glucocorticoid and Androgen Receptor Activation in Salivary Duct Carcinoma.

PURPOSE: To determine the expression of glucocorticoid receptor (GR) and androgen receptor (AR) in salivary duct carcinoma (SDC) and to analyze the role of these proteins in the development and management of this disease entity. EXPERIMENTAL DESIGN: We performed a phenotypic assessment of GR and AR localization and expression, and determined their association with clinicopathologic factors in 67 primary SDCs. In vitro functional and response analysis of SDC cell lines was also performed. RESULTS: Of the 67 primary tumors, 12 (18%) overexpressed GR protein, 30 (45%) had constitutive expression, and 25 (37%) had complete loss of expression. Reciprocal GR and AR expression was found in 32 (48%) tumors, concurrent constitutive GR and AR expression in 23 (34%), and simultaneous loss of both receptors and high GR with AR expressions were found in 12 (18%). GR overexpression was significantly associated with worse clinical outcomes. In vitro ligand-independent AR activation was observed in both male- and female-derived cell lines. GR antagonist treatment resulted in decreased cell proliferation and survival in GR-overexpressing cells, irrespective of AR status. Reciprocal GR- and AR-knockdown experiments revealed an independent interaction. CONCLUSIONS: Our study, for the first time, demonstrates differential GR and AR expressions, autonomous GR and AR activation, and ligand-independent AR expression and activation in SDC cells. The findings provide critical information on the roles of GR and AR steroid receptors in SDC tumorigenesis and development of biomarkers to guide targeted steroid receptor therapy trials in patients with these tumors.

Purulent chondritis of thyroid cartilage.

We report a case of a 77-year-old female with purulent chondritis of the thyroid cartilage who was initially referred for laryngeal neoplasm. Purulent chondritis of the laryngeal cartilage is a rare entity with three reports in the literature. The unique CT imaging features of expansile laryngeal cartilage with peripheral rim enhancement and central fluid-attenuation correlate to the abscess formation between the inner and outer perichondria. The correct imaging assessment prompts surgical management and avoid misdiagnosis.

Ectopic ACTH Production and Cushing's Syndrome in a Patient with Parotid Acinic Cell Carcinoma with High-Grade Transformation: Tumor Context and Clinical Implications.

We report a rare case of Cushing's syndrome in a 59-year-old man who initially presented with concurrent acinic cell carcinoma of the parotid with high-grade transformation and co-existing papillary and medullary thyroid carcinomas, without noticeable cushinoid symptoms. Six-months later, he developed clinical features of Cushing's syndrome which coincided with disease progression in the form of lung metastasis and mediastinal lymphadenopathy. Ectopic adrenocorticotropic hormone (ACTH) production and protein expression was limited to the high-grade transformed component of acinic cell carcinoma and in the lymph node metastasis, and was absent in the conventional acinic cell carcinoma as well as in the papillary and medullary thyroid carcinoma. He received adjuvant chemotherapy and supportive management with interval improvement for 8 months followed by disease progression with increasing serum cortisol levels and bone metastasis. He was offered palliative chemotherapy, however, declined further therapy and was lost to follow up. We discussed clinical and pathologic implications of ectopic ACTH production associated with acinic carcinoma and also reviewed the literature of this rare paraneoplastic syndrome.

Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma.

Acinic cell carcinoma (AcCC) is a morphologically distinctive salivary gland malignancy often associated with chromosome rearrangements leading to overexpression of the NR4A3 transcription factor. However, little is known about how NR4A3 contributes to AcCC biology. Detailed RNA-sequencing of 21 archived AcCC samples revealed fusion reads arising from recurrent t(4;9), t(9;12), t(8;9) or t(2;4) chromosomal translocations, which positioned highly active enhancers adjacent to the promoter of the NR4A3 gene or the closely related NR4A2 gene, resulting in their aberrant overexpression. Transcriptome analyses revealed several distinct subgroups of AcCC tumors, including a subgroup that overexpressed both NR4A3 and MSANTD3. A poor survival subset of the tumors with high-grade transformation expressed NR4A3 and POMC as well as MYB, an oncogene that is the major driver in a different type of salivary gland tumor, adenoid cystic carcinoma. The combination of NR4A3 and MYB showed cooperativity in regulating a distinct set of genes. In addition, the ligand binding domain of NR4A3 directly bound the Myb DNA binding domain. Transformation assays indicated that, while overexpressed NR4A3 was sufficient to generate transformed colonies, the combination of NR4A3 plus Myb was more potent, leading to anchorage-independent growth and increased cellular invasiveness. The results confirm that NR4A3 and NR4A2 are the main driver genes of AcCC and suggest that concurrent overexpression of NR4A3 and MYB defines a subset of AcCC patients with high-grade transformation that display exceptionally poor outcome.

Assessing patient-reported symptom burden of long-term head and neck cancer survivors at annual surveillance in survivorship clinic.

BACKGROUND: This study reports long-term head and neck cancer (HNC) patient-reported symptoms using the MD Anderson Symptom Inventory Head and Neck Cancer Module (MDASI-HN) in a large cohort of HNC survivors. METHODS: MDASI-HN results were prospectively collected from an institutional survivorship database. Associations with clinicopathologic data were analyzed using χ2 , Mann-Whitney, and univariate regression. RESULTS: Nine hundred and twenty-eight patients were included. Forty-six percent had oropharyngeal primary tumors. Eighty-two percent had squamous cell carcinoma. Fifty-six percent of patients had ablative surgery and 81% had radiation therapy as a component of treatment. The most severe symptoms were xerostomia and dysphagia. Symptom scores were worst for hypopharynx and varied by subsite. Patients treated with chemoradiation or surgery followed by radiation ± chemotherapy reported the worst symptoms while patient treated with surgery plus radiation ± chemotherapy reported the worst interference. CONCLUSION: HNC survivors describe their long-term symptom burden and inform efforts to improve care many years into survivorship.

Head and neck surgical oncology in the time of a pandemic: Subsite-specific triage guidelines during the COVID-19 pandemic.

BACKGROUND: COVID-19 pandemic has strained human and material resources around the world. Practices in surgical oncology had to change in response to these resource limitations, triaging based on acuity, expected oncologic outcomes, availability of supportive resources, and safety of health care personnel. METHODS: The MD Anderson Head and Neck Surgery Treatment Guidelines Consortium devised the following to provide guidance on triaging head and neck cancer (HNC) surgeries based on multidisciplinary consensus. HNC subsites considered included aerodigestive tract mucosa, sinonasal, salivary, endocrine, cutaneous, and ocular. RECOMMENDATIONS: Each subsite is presented separately with disease-specific recommendations. Options for alternative treatment modalities are provided if surgical treatment needs to be deferred. CONCLUSION: These guidelines are intended to help clinicians caring for patients with HNC appropriately allocate resources during a health care crisis, such as the COVID-19 pandemic. We continue to advocate for individual consideration of cases in a multidisciplinary fashion based on individual patient circumstances and resource availability.

Current surgical treatment of squamous cell carcinoma of the head and neck.

Historically treatment of head and neck cancers involved surgical resection followed by radiation therapy for advanced tumors. Concurrent chemoradiation therapies have shown equal survival to surgical resection with better preservation of function. However, concurrent therapy does entail significant morbidity, and recent advances have been used to minimize that morbidity. Newer tumor specific medical therapies are anticipated to be less toxic while maintaining a high degree of efficacy. For resectable cancer, transoral laser microsurgery is a new trend in surgery for complete resection of tumors with preservation of function. Advanced reconstructive techniques that allow free transfer of soft tissue and bone from all over the body improve the functional and aesthetic outcomes following major ablative surgery. With successful surgical reconstruction, dental and prosthetic rehabilitation choices are enhanced. Advances in rehabilitation of speech following removal of the larynx have improved the quality of life post-laryngectomy patients. With these newer therapies and methods of reconstruction, each patient needs to be carefully evaluated to maximize the possibility of cure and level of function, and minimize the morbidity associated with treatment. Combined chemotherapy and radiation protocols are associated with increased acute and chronic toxicities that may affect the quality of life due to the impact upon oral disease and oral function. Oral care providers must be aware of advances in cancer management and implications for patient care to effectively care for these patients.

Why Participate in Peer Review as a Journal Manuscript Reviewer: What's in It for You?

The peer review process for scientific journals relies on the efforts of volunteer reviewers. Reviewers are selected due to their expertise in their fields. With so many demands on professional time, the benefits of participating in peer review may not be obvious. However, reviewers benefit by exposure to the latest developments in their fields, facilitating their keeping up-to-date with the latest publications. Tenure committees look favorably on participation in peer review, and invitations to review underscore that the reviewer is a respected subject matter expert. Contacts made during the peer review process can lead to long-lasting collaboration. Continuing medical education credit can be obtained through various mechanisms. Overall, participating in peer review is an important part of career development and should be viewed as a critical component of advancement.

Mucoepidermoid carcinoma post-radioactive iodine treatment of papillary thyroid carcinoma: unique presentation and putative etiologic association.

We report the development of mucoepidermoid carcinomas of the parotid gland in 2 adult patients after a relatively short duration of radioactive iodine (RAI) treatment of papillary thyroid carcinoma. Both instances, together with those previously reported, underscore the selective nature of the mucoepidermoid carcinoma phenotype development in patients with papillary thyroid carcinoma as a consequence of RAI treatment. Efforts to alleviate salivary pathophysiologic damage by RAI in these patients are warranted.

Methylene blue and parathyroid adenoma localization: Three new cases of a rare cutaneous complication.

Methylene blue has been safely used for the localization of parathyroid glands during parathyroidectomy, and only a few adverse effects have been documented. Methylene blue administration as a cause of pulse-oximetry-related skin injury is extremely rare. We describe 2 such cases in patients who developed a blister on the second digit at the pulse oximetry site after an uncomplicated excision of a parathyroid adenoma. In another case, a patient became bradycardic intraoperatively; she was successfully resuscitated, but she incurred a second-degree burn at the pulse oximetry site. In all 3 cases, the burns resolved with local wound care. We publish this report to alert surgeons and anesthesiologists to the risk of skin complications with the use of high-dose intraoperative methylene blue.

Matched-pair analysis of survival of never smokers and ever smokers with squamous cell carcinoma of the head and neck.

PURPOSE: To compare survival rates between patients with squamous cell carcinoma of the head and neck (SCCHN) without a history of smoking (never smokers) and those with a current or previous history of smoking (ever smokers). PATIENTS AND METHODS: Fifty never smokers with newly diagnosed SCCHN were matched to 50 ever smokers according to sex, age, tumor site, overall stage, nodal stage, and treatment. Survival analysis was performed using Kaplan-Meier estimates. Matched-pair survival was compared using the Cox proportional hazards model. RESULTS: The never smokers had a greater overall survival (P =.020), disease-specific survival (P =.022), and recurrence-free survival (P =.016). Furthermore, matched-pair analysis demonstrated smoking was associated with a significant increase in risk of overall death (relative risk [RR] = 3.50; 95% CI, 1.14 to 10.77; P =.029), risk of death owing to disease (RR = 3.98; 95% CI, 1.11 to 14.33; P =.034), and risk of disease recurrence (RR = 3.29; 95% CI, 1.18 to 9.14; P =.023). Smoking was associated with three-fold increases in risk for overall death, death owing to disease, and recurrence after adjustment for cancer-associated symptom severity and alcohol use, but the 95% CI for these adjusted risk estimates each included the null. CONCLUSION: Survival differed significantly between never smokers and ever smokers with SCCHN. These results are not substantively explained by differences in cancer-associated symptoms or alcohol use, but the CIs are wide and some imprecision remains. Regardless, possible fundamental differences in SCCHN between ever smokers and never smokers may exist, and further molecular characterization of these tumors is needed to determine whether biologic differences needing targeted therapies exist.

Matched analysis of survival in patients with squamous cell carcinoma of the head and neck diagnosed before and after 40 years of age.

OBJECTIVES: To compare the survival rates of patients 40 years or younger and diagnosed with squamous cell carcinoma of the head and neck (SCCHN) with those of patients older than 40 years who underwent the same treatment. In 2 previous matched-pair analyses, the patients had been matched for tumor stage, site, sex, and date of presentation but not type of treatment. METHODS: Between 1995 and 2001, 46 patients 40 years or younger participated in a prospective epidemiologic study that included more than 500 patients newly diagnosed with SCCHN. We matched each of these patients by sex, race, tumor site, overall stage, and treatment modality with 2 patients older than 40 years. Ultimately, 31 of the younger patients were matched with 62 of the older patients. Survival analysis was performed using Cox proportional hazard models and accounting for the matched trios. RESULTS: There was no difference in overall, disease-specific, or recurrence-free survival rates between the patients who were 40 years or younger and those older than 40 years. Furthermore, matched survival analysis did not demonstrate a difference in overall survival rate (risk ratio [RR], 0.71; 95% confidence interval [CI], 0.22-2.29; P =.56), disease-free survival rate (RR, 0.83; 95% CI, 0.20-3.33; P =.79), or time to recurrence (RR, 1.46; 95% CI, 0.50-4.23; P =.49), and was not affected by adjustment for medical comorbidities or the severity of cancer-associated symptoms. CONCLUSIONS: We found no evidence of a difference in the survival rates of patients with SCCHN who were 40 years or younger or older than 40 years and underwent similar treatment at our institution.

Complication rate of transtemporal hydroxyapatite cement cranioplasties: a case series review of 76 cranioplasties.

OBJECTIVE: The objective of this study was to evaluate the complication rate of transtemporal cranioplasties using hydroxyapatite cement (HAC) for repair. STUDY DESIGN: We conducted a retrospective case review of patients receiving HAC cranioplasties in the Acoustic Neuroma and Skull Base Surgery Program between July 1998 and December 2002. SETTING: This study was conducted at a tertiary referral center. PATIENTS: A total of 76 HAC cranioplasties were performed in 72 patients undergoing lateral skull base surgery. Patients undergoing anterior skull base surgery or those in which HAC was used for other reconstructive purposes were excluded from the study. INTERVENTIONS: We studied transtemporal approaches for otologic procedures requiring cranioplasty. MAIN OUTCOME MEASURES: Main outcomes measures consisted of complications requiring medical or surgical intervention. RESULTS: Of the 76 HAC cranioplasties, two cranioplasty grafts became infected, requiring explantation. The first case involved a wound infection that extended into and involved the HAC graft; the second involved seeding of the HAC graft after meningitis after a percutaneous, endoscopic gastrostomy tube placement performed several days after the primary skull base surgery. This gives our series a wound infection incidence rate of 1.3% and an overall complication incidence rate of 2.63%. CONCLUSIONS: This retrospective review provides the largest series to date evaluating the incidence of infection in HAC cranioplasties. Despite having a much larger series, our complication rate is the lowest published rate of HAC cranioplasty explantation, and the incidence of superficial wound infections reported here is consistent with the published data for neurosurgical and neurotologic procedures.

Epidemiology of HPV-associated oropharyngeal cancer.

Squamous cell carcinoma of the oropharynx is increasing in incidence in epidemic proportion. This site specific increase in incidence is due to an increase in human papillomavirus (HPV)-related squamous cell carcinoma, while the incidence of tobacco related squamous cell carcinoma is decreasing. In particular, the incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) is increased among middle aged white men, and sexual behavior is a risk factor. HPV-related oropharyngeal squamous cell carcinoma represents a growing etiologically distinct subset of head and neck cancers with unique epidemiological, clinical, and molecular characteristics that differ from those of HPV-unassociated cancers. In this review, we discuss the epidemiology of HPV-related OPSCC, the prevalence of oral/oropharyngeal HPV infection, and efforts aimed at reducing the incidence of HPV-related OPSCC.