David W. Eisele

Treatment is complex for patients with head and neck (H&N) cancers with specific site of disease, stage, and pathologic findings guiding treatment decision-making. Treatment planning for H&N cancers involves a multidisciplinary team of experts. This article describes supportive care recommendations in the NCCN Guidelines for Head and Neck Cancers, as well as the rationale supporting a new section on imaging recommendations for patients with H&N cancers. This article also describes updates to treatment recommendations for patients with very advanced H&N cancers and salivary gland tumors, specifically systemic therapy recommendations.

Abstract Purpose: Oral fluid (saliva) meets the demand for noninvasive, accessible, and highly efficient diagnostic medium. Recent discovery that a large panel of human RNA can be reliably detected in saliva gives rise to a novel clinical approach, salivary transcriptome diagnostics. The purpose of this study is to evaluate the diagnostic value of this new approach by using oral squamous cell carcinoma (OSCC) as the proof-of-principle disease. Experimental Design: Unstimulated saliva was collected from patients (n = 32) with primary T1/T2 OSCC and normal subjects (n = 32) with matched age, gender, and smoking history. RNA isolation was done from the saliva supernatant, followed by two-round linear amplification with T7 RNA polymerase. Human Genome U133A microarrays were applied for profiling human salivary transcriptome. The different gene expression patterns were analyzed by combining a t test comparison and a fold-change analysis on 10 matched cancer patients and controls. Quantitative polymerase chain reaction (qPCR) was used to validate the selected genes that showed significant difference (P < 0.01) by microarray. The predictive power of these salivary mRNA biomarkers was analyzed by receiver operating characteristic curve and classification models. Results: Microarray analysis showed there are 1,679 genes exhibited significantly different expression level in saliva between cancer patients and controls (P < 0.05). Seven cancer-related mRNA biomarkers that exhibited at least a 3.5-fold elevation in OSCC saliva (P < 0.01) were consistently validated by qPCR on saliva samples from OSCC patients (n = 32) and controls (n = 32). These potential salivary RNA biomarkers are transcripts of IL8, IL1B, DUSP1, HA3, OAZ1, S100P, and SAT. The combinations of these biomarkers yielded sensitivity (91%) and specificity (91%) in distinguishing OSCC from the controls. Conclusions: The utility of salivary transcriptome diagnostics is successfully demonstrated in this study for oral cancer detection. This novel clinical approach could be exploited to a robust, high-throughput, and reproducible tool for early cancer detection. Salivary transcriptome profiling can be applied to evaluate its usefulness for other major disease applications as well as for normal health surveillance.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) are a statement of consensus of the authors regarding their views of currently accepted approaches

To explore the potential of tumor-specific DNA as a biomarker for head and neck squamous cell carcinomas (HNSCC), we queried DNA from saliva or plasma of 93 HNSCC patients. We searched for somatic mutations or human papillomavirus genes, collectively referred to as tumor DNA. When both plasma and saliva were tested, tumor DNA was detected in 96% of 47 patients. The fractions of patients with detectable tumor DNA in early- and late-stage disease were 100% (n = 10) and 95% (n = 37), respectively. When segregated by site, tumor DNA was detected in 100% (n = 15), 91% (n = 22), 100% (n = 7), and 100% (n = 3) of patients with tumors of the oral cavity, oropharynx, larynx, and hypopharynx, respectively. In saliva, tumor DNA was found in 100% of patients with oral cavity cancers and in 47 to 70% of patients with cancers of the other sites. In plasma, tumor DNA was found in 80% of patients with oral cavity cancers, and in 86 to 100% of patients with cancers of the other sites. Thus, saliva is preferentially enriched for tumor DNA from the oral cavity, whereas plasma is preferentially enriched for tumor DNA from the other sites. Tumor DNA in saliva was found postsurgically in three patients before clinical diagnosis of recurrence, but in none of the five patients without recurrence. Tumor DNA in the saliva and plasma appears to be a potentially valuable biomarker for detection of HNSCC.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus-associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

Overview This shortened version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck (H&N) Cancers addresses tumors arising in the oral cavity, oropharynx, hypopharynx, and nasopharynx (see Figure 1).1 Other types of H&N cancer (e.g., lip, larynx, paranasal sinus, salivary gland, mucosal melanoma, and occult primary cancer) are included in the complete version of the H&N guidelines available on the NCCN Web site NCCN

Human papillomavirus (HPV) is etiologically responsible for a distinct subset of head and neck squamous cell cancers (HNSCCs). HPV-positive HNSCCs (HPV-HNSCCs) most commonly arise from the oropharynx and are responsible for the increasing incidence of oropharyngeal SCC (OSCC) in the United States (US) and abroad. HPV-positive OSCC (HPV-OSCC) has a unique demographic and risk factor profile and tumor biology. HPV-OSCC patients tend to be white, younger, and have a higher cumulative exposure to sexual behaviors as compared with HPV-negative OSCC patients. HPV-positive tumor status also significantly improves survival, and is indeed the single strongest prognostic factor for OSCC. The mechanisms that underlie the improved prognosis conferred by HPV-positive disease are unknown. The purpose of this review is to describe the clinical impact of HPV status in HNSCC, particularly in OSCC, both in terms of the unique clinic-demographic profile and prognostic implications.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

BACKGROUND Human papillomavirus (HPV) is a well‐established prognostic marker for oropharyngeal squamous cell cancer (OPSCC). Because of the limited numbers of women and nonwhites in studies to date, sex and racial/ethnic differences in prognosis have not been well explored. In this study, survival differences were explored by the tumor HPV status among 1) patients with OPSCCs by sex and race and 2) patients with nonoropharyngeal (non‐OP) head and neck squamous cell cancers (HNSCCs). METHODS This retrospective, multi‐institution study included OPSCCs and non‐OP HNSCCs of the oral cavity, larynx, and nasopharynx diagnosed from 1995 to 2012. Race/ethnicity was categorized as white non‐Hispanic, black non‐Hispanic, Asian non‐Hispanic, and Hispanic of any race. Tumors were centrally tested for p16 overexpression and the presence of HPV by HPV16 DNA and high‐risk HPV E6/E7 messenger RNA in situ hybridization. Kaplan‐Meier and Cox proportional hazards models were used to evaluate overall survival (OS). RESULTS The study population included 239 patients with OPSCC and 621 patients with non‐OP HNSCC with a median follow‐up time of 3.5 years. After adjustments for the tumor HPV status, age, current tobacco use, and stage, the risk of death was lower for women versus men with OPSCC (adjusted hazard ratio, 0.55; P = .04). The results were similar with p16. In contrast, for non‐OP HNSCCs, HPV positivity, p16 positivity, and sex were not associated with OS. CONCLUSIONS For OPSCC, there are differences in survival by sex, even after the tumor HPV status has been taken into account. For non‐OP HNSCC, the HPV status and the p16 status are not of prognostic significance. Cancer 2017;123:1566–1575. © 2017 American Cancer Society .

Hypoglossal nerve stimulation has been demonstrated to relieve upper airway obstruction acutely, but its effect on obstructive sleep apnea is not known.To determine the response in obstructive sleep apnea to electrical stimulation of the hypoglossal nerve.Eight patients with obstructive sleep apnea were implanted with a device that stimulated the hypoglossal nerve unilaterally during inspiration. Sleep and breathing patterns were examined at baseline before implantation and after implantation at 1, 3, and 6 months and last follow-up.Unilateral hypoglossal nerve stimulation decreased the severity of obstructive sleep apnea throughout the entire study period. Specifically, stimulation significantly reduced the mean apnea-hypopnea indices in non-rapid eye movement (mean +/- SD episodes per hour, 52.0 +/- 20.4 for baseline nights and 22.6 +/- 12.1 for stimulation nights; P<.001) and rapid eye movement (48.2 +/- 30.5 and 16.6 +/- 17.1, respectively; P<.001) sleep and reduced the severity of oxyhemoglobin desaturations. With improvement in sleep apnea, a trend toward deeper stages of non-rapid eye movement sleep was observed. Moreover, all patients tolerated long-term stimulation at night and did not experience any adverse effects from stimulation. Even after completing the study protocol, the 3 patients who remained free from stimulator malfunction continued to use this device as primary treatment.The findings demonstrate the feasibility and therapeutic potential for hypoglossal nerve stimulation in obstructive sleep apnea.

This study sought to review a single-institution experience with the management of adenoid cystic carcinoma of the head and neck.Between 1960 and 2004, 140 patients with adenoid cystic carcinoma of the head and neck were treated with definitive surgery. Ninety patients (64%) received postoperative radiation to a median dose of 64 Gy (range, 54-71 Gy). Distribution of T stage was: 26% T1, 28% T2, 20% T3, and 26% T4. Seventy-eight patients (56%) had microscopically positive margins. Median follow-up was 66 months (range, 7-267 months).The 5- and 10-year rate estimates of local control were 88% and 77%, respectively. A Cox proportional hazards model identified T4 disease (p = 0.0001), perineural invasion (p = 0.008), omission of postoperative radiation (p = 0.007), and major nerve involvement (p = 0.02) as independent predictors of local recurrence. Radiation dose lower than 60 Gy (p = 0.0004), T4 disease (p = 0.005), and major nerve involvement (p = 0.02) were predictors of local recurrence among those treated with surgery and postoperative radiation. The 10-year overall survival and distant metastasis-free survival were 64% and 66%, respectively.Combined-modality therapy with surgery followed by radiation to doses in excess of 60 Gy should be considered the standard of care for adenoid cystic carcinoma of the head and neck.

To determine the motor responses resulting from direct electrical stimulation of the hypoglossal (HG) nerve and to correlate these responses to changes in upper airway patency during sleep.The motor effects of direct electrical stimulation of the main trunk of the HG nerve and the branch that supplies the genioglossus muscle during anesthesia and wakefulness were assessed visually. Responses in airflow during sleep to HG nerve stimulation were assessed with standard polysomnographic techniques.University medical center.Fifteen patients undergoing a surgical procedure that involved the neck that exposed the HG nerve and 5 volunteer patients with obstructive sleep apnea constituted the study population.The main trunk (n = 3) and genioglossus branch (n = 2) of the HG nerve were stimulated electrically with a half-cuff tripolar electrode.Stimulation of the branch of the HG nerve that innervates the genioglossus muscle caused protrusion and contralateral deviation of the tongue. Stimulation of the main trunk of the HG nerve caused slight ipsilateral deviation and retrusion of the tongue. The arousal threshold for stimulation exceeded the motor recruitment threshold by 0.8 +/- 0.4 V. Inspiratory airflow increased in all patients by 184.5 +/- 61.7 mL/s (mean +/- SD; P = .02, analysis of variance) with stimulation.Direct HG nerve stimulation below the arousal threshold can improve airflow in patients with obstructive sleep apnea.

The influence of lingual muscle activity on airflow dynamics in the upper airway was examined in nine patients with obstructive sleep apnea. Muscles that retract the tongue (hyoglossus and styloglossus) and protrude the tongue (genioglossus) were selectively stimulated electrically during sleep with fine wire electrodes placed intramuscularly transorally. We confirmed that stimulation with 50 Hz and 40-microseconds pulse duration did not elicit changes in electroencephalographic patterns or heart rate or alter airflow after the stimulation burst had ceased. The highest stimulus intensity that did not arouse patients from sleep was then utilized to examine the effect of lingual muscle recruitment on airflow dynamics during steady-state periods of inspiratory airflow limitation. When applying a stimulus burst during single inspirations, maximal inspiratory airflow decreased by 239 +/- 177 ml/s (P < 0.05) during retractor stimulation, whereas maximal inspiratory airflow increased by 217 +/- 93 ml/s during protrusor stimulation (P < 0.001) compared with breaths immediately before and after the stimulated breath. When consecutive inspirations were stimulated repeatedly, protrusor stimulation decreased the frequency of obstructive breathing episodes in four patients breathing at 3.9 +/- 3.4 (SD) cmH2O nasal pressure. The findings suggest that stimulation of the lingual muscles can increase or decrease airflow depending on the specific muscles stimulated without arousing patients from sleep.

In patients with head and neck squamous cell carcinoma (HNSCC), a squamous cell carcinoma (SCC) in the lung represents either another primary tumor or a metastasis. This distinction greatly influences patient prognosis and could guide treatment strategies, but the nature of a solitary lung nodule is often difficult to discern by use of standard clinical and histologic parameters. Comparison of genetic alterations in the tumors could resolve this dilemma.We compared paired tumors from 16 patients with HNSCC and a solitary lung SCC for loss (i.e., deletion) of loci on chromosomal arms 3p and 9p. Losses at these loci occur early during neoplastic transformation of the respiratory tract. DNA from microdissected tumors and normal tissues was subjected to polymerase chain reaction-based microsatellite analysis. An effort was also made to distinguish primary lung cancers from lung metastases on the basis of clinical and histopathologic features.In most cases, comparison of genetic alterations clarified the relationship between the lung tumor and the primary HNSCC. The paired tumors from 10 patients had concordant patterns of loss at all loci suggesting metastatic spread, whereas three paired tumors had discordant patterns of loss at all loci suggesting independent tumor origin. These observations were supported by the clinical and pathologic findings.In patients with HNSCC and a solitary SCC in the lung, microsatellite analysis provides a rapid genetic approach for discerning clonal relationships. In such patients, we found that a solitary SCC in the lung more likely represents a metastasis than an independent lung cancer. Microsatellite analysis could potentially be applied to any patient with multiple tumors, where tumor relationships are not clear on clinical, radiographic, or even histopathologic grounds.

Previous investigators have demonstrated variable responses to uvulopalatopharyngoplasty (UPP) in patients with obstructive sleep apnea. We hypothesized that this variability is due to either (1) differences in baseline pharyngeal collapsibility preoperatively or (2) differences in magnitude of the decrease in pharyngeal collapsibility resulting from surgery. To determine the relationship between changes in collapsibility and the response to UPP surgery, we measured the upper airway critical pressure (Pcrit) before and after UPP in 13 patients with obstructive sleep apnea. During non-REM sleep, maximal inspiratory airflow (VImax) was quantitated by varying the level of nasal pressure (PN), and Pcrit was determined by the level of PN below which VImax ceased. A positive response to UPP was defined by a greater than or equal to 50% fall in non-REM disordered breathing rate (DBR). In the entire group, UPP resulted in significant decreases in DBR from 71.1 +/- 22.4 to 44.7 +/- 38.4 episodes/h (p = 0.025) and in Pcrit from 0.2 +/- 2.4 to -3.1 +/- 5.4 cm H2O (p = 0.016). Moreover, the percent change in DBR was correlated significantly with the change in Pcrit (p = 0.001). Subgroup analysis of responders and nonresponders demonstrated that significant differences in Pcrit were confined to the responders. Specifically, responders demonstrated a significant fall in Pcrit from -0.8 +/- 3.0 to -7.3 +/- 4.9 cm H2O (p = 0.01), whereas no significant change in Pcrit was detected in the nonresponders (1.1 +/- 1.6 versus 0.6 +/- 2.0 cm H2O. No clinical, polysomnographic, or physiologic predictors of a favorable response were found preoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Acinic cell carcinoma (ACC) is a low-grade salivary gland malignancy characterized by serous acinar differentiation. Most ACCs arise in the parotid gland, but ACCs have been reported to originate in nonparotid salivary glands where serous acini are less abundant. Given the recent discovery of mammary analog secretory carcinoma (MASC)—a salivary malignancy that histologically mimics ACC—a retrospective reevaluation of nonparotid ACCs is warranted. The surgical pathology archives of The Johns Hopkins Hospital were searched for all ACCs arising outside of the parotid gland. For each case, the histologic slides were reviewed; immunohistochemical analysis (mammaglobin, S100 protein) was performed; and confirmatory ETV6 breakapart fluorescence in situ hybridization assay was completed. Demographic and clinical data were obtained from the medical records. Fourteen extraparotid tumors diagnosed as ACC were identified. Eleven of 14 (79%) tumors harbored the ETV6 translocation (oral cavity=9 of 11; submandibular gland=2 of 2). The translocation-positive tumors occurred in 7 women and 4 men ranging in age from 20 to 86 years (mean, 56 y) and usually presented as painless masses. Immunohistochemistry for mammaglobin and S100 was positive in all 11 translocation-positive tumors but negative in the 3 translocation-negative tumors. Histologically, the translocation-positive tumors exhibited uniform cells with vacuolated cytoplasm, microcystic/cystic and papillary architecture, and intraluminal secretions; however, the presence of basophilic cytoplasmic granules was conspicuously absent. Basophilic cytoplasmic granules, indicative of true serous acinar differentiation, were present in the 3 translocation-negative tumors. Of the translocation-positive tumors, only 1 locally recurred, and none metastasized. Most alleged ACCs of nonparotid origin actually represent misclassified MASCs. The impact of diagnostic error is mitigated by the low-grade nature of MASC that, like ACCs, do not appear to be clinically aggressive.

To report the clinical outcome of patients treated with intensity-modulated radiation therapy (IMRT) for malignancies of the nasal cavity and paranasal sinuses.Between 1998 and 2004, 36 patients with malignancies of the sinonasal region were treated with IMRT. Thirty-two patients (89%) were treated in the postoperative setting after gross total resection. Treatment plans were designed to provide a dose of 70 Gy to 95% or more of the gross tumor volume (GTV) and 60 Gy to 95% or more of the clinical tumor volume (CTV) while sparing neighboring critical structures including the optic chiasm, optic nerves, eyes, and brainstem. The primary sites were: 13 ethmoid sinus, 10 maxillary sinus, 7 nasal cavity, and 6 other. Histology was: 12 squamous cell, 7 esthesioneuroblastoma, 5 adenoid cystic, 5 undifferentiated, 5 adenocarcinoma, and 2 other. Median follow-up was 51 months among surviving patients (range, 9-82 months).The 2-year and 5-year estimates of local control were 62% and 58%, respectively. One patient developed isolated distant metastasis, and none developed isolated regional failure. The 5-year rates of disease-free and overall survival were 55% and 45%, respectively. The incidence of ocular toxicity was minimal with no patients reporting decreased vision. Late complications included xerophthalmia (1 patient), lacrimal stenosis (1 patient), and cataract (1 patient).Although IMRT for malignancies of the sinonasal region does not appear to lead to significant improvements in disease control, the low incidence of complications is encouraging.

Mammary analogue secretory carcinoma is a recently described salivary gland neoplasm defined by ETV6-NTRK3 gene fusion. Mammary analogue secretory carcinoma's morphology is not entirely specific and overlaps with other salivary gland tumors. Documenting ETV6 rearrangement is confirmatory, but most laboratories are not equipped to perform this test. As mammary analogue secretory carcinomas are positive for mammaglobin, immunohistochemistry could potentially replace molecular testing as a confirmatory test, but the specificity of mammaglobin has not been evaluated across a large and diverse group of salivary gland tumors. One hundred thirty-one salivary gland neoplasms were evaluated by routine microscopy, mammaglobin immunohistochemistry, and ETV6 break-apart fluorescent in situ hybridization. The cases included 15 mammary analogue secretory carcinomas, 44 adenoid cystic carcinomas, 33 pleomorphic adenomas, 18 mucoepidermoid carcinomas, 10 acinic cell carcinomas, 4 adenocarcinomas not otherwise specified, 3 polymorphous low-grade adenocarcinomas, 3 salivary duct carcinomas, and 1 low-grade cribriform cystadenocarcinoma. All 15 mammary analogue secretory carcinomas harbored the ETV6 translocation and were strongly mammaglobin positive. None of the 116 other tumors carried the ETV6 translocation; however, mammaglobin staining was present in 1 (100%) of 1 low-grade cribriform cystadenocarcinoma, 2 (67%) of 3 polymorphous low-grade adenocarcinomas, 2 (67%) of 3 salivary duct carcinomas, 2 (11%) of 18 mucoepidermoid carcinomas, and 2 (6%) of 33 pleomorphic adenomas. Mammaglobin is highly sensitive for mammary analogue secretory carcinoma, but immunostaining can occur in a variety of tumors that do not harbor the ETV6 translocation. Strategic use of mammaglobin immunostaining has a role in the differential diagnosis of salivary gland neoplasms, but it should not be indiscriminately used as a confirmatory test for mammary analogue secretory carcinoma.

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

I. Principles of Facial Plastic and Reconstructive Surgery: Anatomy and Physiology of the Skin Wound Healing Soft Tissue Techniques Skin Grafts and Flaps Scar Revision Synthetic Implants Biologic Tissue Implants Lasers in Facial Plastic Surgery Aesthetic Facial Proportions Computer Imaging in Facial Plastic Surgery Photography in Facial Plastic Surgery Ethics in Facial Plastic Surgery. II. Aesthetic Facial Surgery: Aesthetic Facial Analysis Anesthesia for Facial Plastic Surgery Rhytidectomy Surgical Treatment of the Forehead, Brow, and Midface Upper Eyelid Blepharoplasty Lower Eyelid Blepharoplasty Lipectomy of the Face, Head, and Neck Dermabrasion and Chemical Peel Laser Facial Resurfacing Injectable and Implantable Materials for Facial Wrinkles Aesthetic Facial Skeletal Implants Aesthetic Facial Implants Hair Replacement Techniques Otoplasty The Asian Face in Facial Plastic Surgery Aesthetic Surgery of the Lip Aesthetic Dentistry. III. Functional and Aesthetic Surgery of the Nose: Analysis in Rhinoplasty Philosophy and Principles of Rhinoplasty External Rhinoplasty Approach Management of the Bony Nasal Vault Management of the Middle Vault Surgery of the Nasal Tip: Intranasal Approach Surgery of the Nasal Tip: Vertical Dome Division Secondary Rhinoplasty Complications of Rhinoplasty Nasal Septal Surgery Management of Nasal Septal Perforations. IV. Reconstructive Surgery of the Face and Neck: Cutaneous Malignancies Grafts and Minimally Invasive Options for Cutaneous Reconstruction Local Cutaneous Flaps Tissue Expansion Musculocutaneous Flaps Microvascular Flaps Mandible Reconstruction Major Nasal Reconstruction Auricular Reconstruction and Temporoparietal Flaps Lip Reconstruction Periocular Reconstruction Management and Reanimation of the Paralyzed Face. V. Trauma: Soft Tissue Injuries of the Face Fundamentals of Bone Healing and Stabilization Bone Plating Systems Clinical Applications of Bone Plating Systems to Facial Fractures Treatment of Orbitozygomatic Fractures Nasal, Frontal Sinus, and Nasorbitoethmoid Complex Fractures Le Fort Fractures (Maxillary Fractures) Mandibular Fractures. VI. Congenital and Pediatric Facial Plastic Surgery: Embryology of the Face, Head, and Neck Craniomaxillofacial Deformities Microtia Reconstruction Cleft Lip and Palate Cleft Lip Rhinoplasty Orthognathic Surgery Hemifacial Microsomia Velopharyngeal Incompetence.

To compare clinical outcomes of patients with carcinomas of the paranasal sinuses and nasal cavity according to decade of radiation treatment.Between 1960 and 2005, 127 patients with sinonasal carcinoma underwent radiotherapy with planning and delivery techniques available at the time of treatment. Fifty-nine patients were treated by conventional radiotherapy; 45 patients by three-dimensional conformal radiotherapy; and 23 patients by intensity-modulated radiotherapy. Eighty-two patients (65%) were treated with radiotherapy after gross total tumor resection. Nineteen patients (15%) received chemotherapy. The most common histology was squamous cell carcinoma (83 patients).The 5-year estimates of overall survival, local control, and disease-free survival for the entire patient population were 52%, 62%, and 54%, respectively. There were no significant differences in any of these endpoints with respect to decade of treatment or radiotherapy technique (p > 0.05, for all). The 5-year overall survival rate for patients treated in the 1960s, 1970s, 1980s, 1990s, and 2000s was 46%, 56%, 51%, 53%, and 49%, respectively (p = 0.23). The observed incidence of severe (Grade 3 or 4) late toxicity was 53%, 45%, 39%, 28%, and 16% among patients treated in the 1960s, 1970s, 1980s, 1990s, and 2000s, respectively (p = 0.01).Although we did not detect improvements in disease control or overall survival for patients treated over time, the incidence of complications has significantly declined, thereby resulting in an improved therapeutic ratio for patients with carcinomas of the paranasal sinuses and nasal cavity.

Abstract BACKGROUND. Treatment outcomes for stage III and IV oropharyngeal carcinoma treated with intensity‐modulated radiotherapy (IMRT) and concurrent chemotherapy without prior surgical resection were reviewed. METHODS. Between April 2000 and September 2004, 71 patients underwent IMRT concurrent with chemotherapy without prior surgical resection for stage III and IV oropharyngeal carcinoma. Chemotherapy was platinum based. The gross tumor volume (GTV) received 70 Gy in 2.12 Gy per fraction. The high‐risk clinical tumor volume (CTV) received 59.4 Gy in 1.80 Gy per fraction, and the low‐risk CTV received 54 Gy in 1.64 Gy per fraction. RESULTS. With a median follow‐up of 33 months, the 3‐year local, regional, and locoregional progression‐free probabilities were 94%, 94%, and 90%, respectively. The 3‐year overall survival estimate was 83%. Locoregional failures occurred in the GTV in 7 patients. Acute grade 3 or 4 toxicity developed in 35 patients. A feeding gastrostomy was placed in 25 patients. Late xerostomia was grade 0 in 16 patients, grade 1 in 31 patients, and grade 2 in 24 patients at last follow‐up. No patients experienced grade 3 or 4 late toxicity, except for 1 who developed osteoradionecrosis of the mandible. CONCLUSIONS. Excellent local and regional control was achieved with IMRT and concurrent chemotherapy without prior surgical resection in the treatment of stage III and IV oropharyngeal carcinoma. Significant sparing of the parotid glands and other critical normal tissues was possible using IMRT with moderate acute toxicities and minimal severe late effects. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND Human papillomavirus (HPV) tumor status and surgical salvage are associated with improved prognosis for patients with recurrent oropharyngeal squamous cell carcinoma (OPSCC). Current data regarding types of surgery and the impact of surgery for patients with distant metastatic disease are limited. METHODS A retrospective analysis of patients with recurrent OPSCC from 2 institutions between 2000 and 2012 was performed. p16 immunohistochemistry and/or in situ hybridization, as clinically available, were used to determine HPV tumor status. Clinical characteristics, distribution of recurrence site, and treatment modalities were compared by HPV tumor status. Overall survival (OS) was examined using Kaplan‐Meier and Cox proportional hazards methods. RESULTS The current study included 108 patients with 65 locoregional and 43 distant metastatic first recurrences. The majority of patients were HPV‐positive (80 patients). HPV‐positive tumor status was associated with longer time to disease recurrence ( P &lt;.01). Anatomic site distribution of disease recurrences did not differ by HPV tumor status. HPV‐positive tumor status (adjusted HR [aHR], 0.23; 95% confidence interval [95% CI], 0.09‐0.58 [ P = .002]), longer time to disease recurrence (≥1 year; aHR, 0.36; 95% CI, 0.18‐0.74 [ P = .006]), and surgical salvage (aHR, 0.26; 95% CI, 0.12‐0.61 [ P = .002]) were found to be independently associated with OS after disease recurrence. Surgical salvage was independently associated with improved OS compared with nonsurgical treatment among patients with both locoregional (aHR, 0.15; 95% CI, 0.04‐0.56 [ P = .005]) and distant (aHR, 0.19; 95% CI, 0.05‐0.75 [ P = .018]) metastatic disease recurrences. CONCLUSIONS Surgical salvage was found to be associated with improved OS for patients with recurrent locoregional and distant metastatic OPSCC, independent of HPV tumor status. Further prospective data are needed to confirm the role of surgical salvage for distant metastases. Cancer 2015;121:1977–1984. © 2015 American Cancer Society .

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients.In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models.Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status.The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.

Human papillomavirus (HPV) causes an increasing proportion of oropharyngeal squamous cell carcinomas (OPSCCs), particularly in white men. The prevalence of HPV among other demographic groups and other anatomic sites of HNSCC is unclear.To explore the role of HPV tumor status among women and nonwhites with OPSCC and patients with nonoropharyngeal head and neck squamous cell carcinoma (non-OP HNSCC).Retrospective cohort study at 2 tertiary academic centers including cases diagnosed 1995 through 2012, oversampled for minorities and females. A stratified random sample of 863 patients with newly diagnosed SCC of the oral cavity, oropharynx, larynx, or nasopharynx was used.Outcomes were HPV status as measured by p16 immunohistochemical analysis, HPV16 DNA in situ hybridization (ISH), and high-risk HPV E6/E7 mRNA ISH.Of 863 patients, 551 (63.9%) were male and median age was 58 years (interquartile range, 51-68 years). Among 240 OPSCCs, 144 (60%) were p16 positive (p16+), 115 (48%) were HPV16 DNA ISH positive (ISH16+), and 134 (56%) were positive for any oncogenic HPV type (ISH+). From 1995 to 2012, the proportion of p16+ OPSCC increased significantly among women (from 29% to 77%; P = .005 for trend) and men (36% to 72%; P < .001 for trend), as well as among whites (39% to 86%; P < .001 for trend) and nonwhites (32% to 62%; P = .02 for trend). Similar results were observed for ISH+ OPSCC (P ≤ .01 for all). Among 623 non-OP HNSCCs, a higher proportion were p16+ compared with ISH positive (62 [10%] vs 30 [5%]; P = .001). A high proportion (26 of 62 [42%]) of these p16+ non-OP HNSCCs were found in sites adjacent to the oropharynx. The proportion of p16+ and ISH+ non-OP HNSCCs were similar by sex. Over time, the proportion of non-OP HNSCCs that were p16+ (or ISH+) increased among whites (P = .04 for trend) but not among nonwhites (each P > .51 for trend). Among OPSCCs, p16 had high sensitivity (100%), specificity (91%), and positive (93%) and negative predictive value (100%) for ISH positivity. In non-OP HNSCCs, p16 had lower sensitivity (83%) and positive predictive value (40%) but high specificity (94%) and negative predictive value (99%) for ISH positivity.During 1995 through 2012, the proportion of OPSCCs caused by HPV has increased significantly. This increase was not restricted to white men but was a consistent trend for women and men, as well as for white and nonwhite racial groups. Few non-OP HNSCCs were HPV related. P16 positivity was a good surrogate for ISH+ tumor status among OPSCC, but not a good surrogate for non-OP HNSCC.

The objective of this review study was to encompass the relevant literature and current best practice options for this challenging, sometimes incurable problem. The source of the data was Ovid MEDLINE from 1946 to 2014. Review methods consisted of articles with clinical correlates. The most important cause of recurrence is enucleation with rupture and incomplete tumor excision at operation. Incomplete pseudocapsule, extracapsular extension, pseudopods of pleomorphic adenoma tissue, and satellite pleomorphic beyond the pseudocapsule are also likely linked to recurrent pleomorphic adenoma. Most recurrent pleomorphic adenoma are multinodular. Magnetic resonance imaging is the imaging study of choice for recurrent pleomorphic adenoma. Nerve integrity monitoring may reduce morbidity for recurrent pleomorphic adenoma. Treatment of recurrent pleomorphic adenoma must be individualized. Total parotidectomy, given the multicentricity of recurrent pleomorphic adenoma, is appropriate in many patients, but may be inadequate to control recurrent pleomorphic. There is accumulating evidence from retrospective series that postoperative radiation therapy results in significantly better local control. Laryngoscope , 125:888–893, 2015

ABSTRACT Background The purpose of this study was to evaluate the current use of transoral robotic surgery (TORS) in the treatment of parapharyngeal space (PPS) neoplasms through a case series and systematic analysis. Methods A case series review of 4 patients was combined with a PubMed, Web of Science, and Scopus search that identified 82 reports. Fifty‐three articles remained after screening for duplicates, finally, 8 reports with adequate patient data were included. Statistical analyses and graphical representations were performed with Microsoft Excel (Redmond, WA) and GraphPad Prism software (La Jolla, CA). Results Forty‐four patients had TORS resection of PPS neoplasms. Overall, mean length of stay was 3.0 days with mean time to oral diet of 1.0 day. There were no recurrences but there was a mean follow‐up time of only 18.5 months. Twenty‐nine of these neoplasms (65.9%) were pleomorphic adenomas of which 7 (24%) had unintended capsule violation or tumor fragmentation during surgery and 2 patients had pharyngeal dehiscence that was managed conservatively. There were no neurovascular complications. Conclusion TORS is a viable approach to resection of neoplasms of the PPS with minimal surgical morbidity. However, further long‐term evaluation, especially for pleomorphic adenomas, is needed to define patient selection and the role of TORS for PPS salivary gland neoplasms. © 2013 Wiley Periodicals, Inc. Head Neck 37 : 293‐298, 2015

The presence of human papillomavirus (HPV) in unknown primary squamous cell carcinoma (UPSCC) of the head and neck at initial presentation focuses the investigation for the primary tumor on the oropharynx. The trends, frequency, and detection rate of UPSCCs have not been evaluated in the context of HPV tumor status.To determine the frequency of UPSCC over time and to evaluate the proportion of HPV-positive UPSCCs.Retrospective, single-institutional case series of patients diagnosed with UPSCC and evaluated at the Johns Hopkins Hospital from January 1, 2005, to June 1, 2014. Human papillomavirus tumor status was determined by p16 immunohistochemical analysis and/or high-risk HPV DNA by in situ hybridization as clinically available.Number and clinical characteristics of UPSCC cases over time.Eighty-four UPSCC cases were eligible for analysis. The mean age of the patients was 57.3 years (range 29-80 years), and 88.1% (n = 74) were male. The frequency of UPSCC increased significantly over time (P for trend = .01) and was significantly higher during later calendar periods (14 cases during 2005-2008 vs 39 cases during 2012-2014, P = .03). A total of 69 cases (90.7%) with available HPV tumor status were HPV-positive. The patients with HPV-positive UPSCC were significantly more likely to be male (91% vs 42.9%, P = .005) and younger (56.1 vs 67.7 years, P = .002) than the HPV-negative patients with UPSCC. The overall primary tumor site detection rate was 59.3% (n = 48). There was a nonsignificant increase in the detection rate from calendar periods 2005-2008 to 2012-2014 (50.0% vs 64.9%, P = .38). Since transoral robotic surgery was adopted in the diagnostic evaluation of UPSCC in 2011, a nonsignificant increase in the detection of primary tumors was observed (53.8% vs 64.3%, P = .34).The frequency of UPSCC has increased significantly in recent calendar periods, and most cases are HPV-positive. As expected, patients with HPV-positive UPSCC tend to be male and younger.

abstract Background Parathyroid scintigraphy using 99m Tc‐MIBI single photon emission computed tomography (SPECT)/CT has been proposed as one of the most accurate localization techniques in patients with primary hyperparathyroidism (PHPT). The purpose of this review was to meta‐analyze published data on the detection rate of 99m Tc‐MIBI SPECT/CT in the preoperative planning of patients with PHPT. Methods A comprehensive literature search of studies published through June 2014 was performed. The pooled detection rate of this scintigraphic method including 95% confidence intervals (95% CIs) was calculated on a per patient‐based and on a per lesion‐based analysis by using a random effects model. Results Twenty‐three articles including 1236 patients with PHPT were selected. The pooled detection rate of 99m Tc‐MIBI SPECT/CT in the preoperative planning of patients with PHPT was 88% (95% CI = 84% to 92%) and 88% (95% CI = 82% to 92%) on a per patient‐based and per lesion‐based analysis, respectively. Conclusion The 99m Tc‐MIBI SPECT/CT has high detection rate for hyperfunctioning parathyroid glands in patients with PHPT. © 2015 Wiley Periodicals, Inc. Head Neck 38 : E2159–E2172, 2016

Objective To determine the relationship between frailty and comorbidity, in‐hospital mortality, postoperative complications, length of hospital stay (LOS), and costs in head and neck cancer (HNCA) surgery. Study Design Cross‐sectional analysis. Methods Discharge data from the Nationwide Inpatient Sample for 159,301 patients who underwent ablative surgery for a malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasm in 2001 to 2010 was analyzed using cross‐tabulations and multivariate regression modeling. Frailty was defined based on frailty‐defining diagnosis clusters from the Johns Hopkins Adjusted Clinical Groups frailty‐defining diagnosis indicator. Results Frailty was identified in 7.4% of patients and was significantly associated with advanced comorbidity (odds ratio [OR] = 1.5[1.3–1.8]), Medicaid (OR = 1.5[1.3–1.8]), major procedures (OR = 1.6[1.4–1.8]), flap reconstruction (OR = 1.7[1.3–2.1]), high‐volume hospitals (OR = 0.7[0.5–1.0]), discharge to a short‐term facility (OR = 4.4[2.9–6.7]), or other facility (OR = 5.4[4.5–6.6]). Frailty was a significant predictor of in‐hospital death (OR = 1.6[1.1–2.4]), postoperative surgical complications (OR = 2.0[1.7–2.3]), acute medical complications (OR = 3.9[3.2–4.9]), increased LOS (mean, 4.9 days), and increased mean incremental costs ($11,839), and was associated with higher odds of surgical complications and increased costs than advanced comorbidity. There was a significant interaction between frailty and comorbidity for acute medical complications and length of hospitalization, with a synergistic effect on the odds of medical complications and LOS in patients with comorbidity who were also frail. Conclusion Frailty is an independent predictor of postoperative morbidity, mortality, LOS, and costs in HNCA surgery patients, and has a synergistic interaction with comorbidity that is associated with an increased likelihood of medical complications and greater LOS in patients with comorbidity who are also frail. Level of Evidence 2c. Laryngoscope , 128:102–110, 2018

Nonsmall cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. About 14% of NSCLCs harbor mutations in epidermal growth factor receptor (EGFR). Despite remarkable progress in treatment with tyrosine kinase inhibitors (TKIs), only 5% of patients achieve tumor reduction >90%. The limited primary responses are attributed partly to drug resistance inherent in the tumor cells before therapy begins. Recent reports showed that activation of receptor tyrosine kinases (RTKs) is an important determinant of this innate drug resistance. In contrast, we demonstrate that EGFR inhibition promotes innate drug resistance despite blockade of RTK activity in NSCLC cells. EGFR TKIs decrease both the mitogen-activated protein kinase (MAPK) and Akt protein kinase pathways for a short time, after which the Ras/MAPK pathway becomes reactivated. Akt inhibition selectively blocks the transcriptional activation of Ets-1, which inhibits its target gene, dual specificity phosphatase 6 (DUSP6), a negative regulator specific for ERK1/2. As a result, ERK1/2 is activated. Furthermore, elevated c-Src stimulates Ras GTP-loading and activates Raf and MEK kinases. These observations suggest that not only ERK1/2 but also Akt activity is essential to maintain Ets-1 in an active state. Therefore, despite high levels of ERK1/2, Ets-1 target genes including DUSP6 and cyclins D1, D3, and E2 remain suppressed by Akt inhibition. Reduction of DUSP6 in combination with elevated c-Src renews activation of the Ras/MAPK pathway, which enhances cell survival by accelerating Bim protein turnover. Thus, EGFR TKIs evoke innate drug resistance by preventing Akt activity and inactivating Ets-1 function in NSCLC cells.

<h3>Importance</h3> Functional status and physiologic deficits independent of age are being recognized for surgical risk stratification. Frailty is expressed as a combination of decreased physiologic reserve and multisystem impairments distinct from normal aging processes. <h3>Objective</h3> To assess the predictive value of the Modified Frailty Index (mFI) for Clavien-Dindo grade IV (CDIV) (intensive care unit–level complications) and grade V (mortality) after major head and neck oncologic surgery. <h3>Design, Setting, and Participants</h3> Retrospective analysis of prospectively collected American College of Surgeons National Surgical Quality Improvement Program data. All major head and neck cancer operations data were obtained from the January 1, 2006, to December 31, 2013, American College of Surgeons National Surgical Quality Improvement Program databases. Fifteen variables composed a previously validated mFI, with higher mFIs identifying more frail patients. Clavien-Dindo grade IV and mortality were defined using a preexisting mapping scheme from the Canadian Study of Health and Aging. Multivariable logistic regression analyses were performed. <h3>Main Outcomes and Measures</h3> The primary outcome measures were Clavien-Dindo Grade IV critical care complications and Grade V complications (mortality). Second outcomes included morbidity, readmission, and reoperation. <h3>Results</h3> There were 1193 major head and neck operations in the American College of Surgeons National Surgical Quality Improvement Program databases, with 86 (7.2%) CDIV complications. The mean (SD) age of all patients was 63.4 (12.4) years, and 67.7% (807 of 1193) were male. Clavien-Dindo grade IV significantly increased from 4.6% (22 of 483) to 100% (1 of 1) from nonfrail to the frailest patients (<i>R2</i> = 0.79,<i>P</i> &lt; .001). Mortality increased with the mFI (but not significantly) from 0.8% (4 of 483) to 3.6% (2 of 55) (<i>R2</i> = 0.46,<i>P</i> = .42). Overall morbidity was not significantly associated or correlated with the mFI. On cross tabulation, increases in the mFI led to more CDIV complications in patients undergoing glossectomy (<i>P</i> = .03), mandibulectomy (<i>P</i> = .02), or laryngectomy (<i>P</i> = .002). Patients undergoing pharyngectomy or esophagectomy did not have significant increases in CDIV complications by the mFI. The coefficients of determination for each category were<i>R2</i> = 0.62 for glossectomy,<i>R2</i> = 0.72 for mandibulectomy,<i>R2</i> = 0.97 for laryngectomy,<i>R2</i> = 0.94 for pharyngectomy, and<i>R2</i> = 1.00 for esophagectomy. On multivariable analysis, the mFI was associated with CDIV complications (odds ratio, 1.65; 95% CI, 1.15-2.37) but not mortality (odds ratio, 0.78; 95% CI, 0.34-1.76). <h3>Conclusions and Relevance</h3> The mFI is predictive of postoperative critical care support after surgery for head and neck cancer. Specifically, increases in mFIs were strongly associated with CDIV complications for glossectomy, mandibulectomy, and laryngectomy. Classifying patients by their functional status using the mFI may help predict outcomes after head and neck oncologic surgery.

The incidence of oropharyngeal cancer (OPC) is significantly increasing in the United States. Given that these epidemiologic trends are driven by human papillomavirus (HPV), the potential impact of prophylactic HPV vaccines on the prevention of OPC is of interest. The primary evidence supporting the approval of current prophylactic HPV vaccines is from large phase 3 clinical trials focused on the prevention of genital disease (cervical and anal cancer, as well as genital warts). These trials reported vaccine efficacy rates of 89% to 98% for the prevention of both premalignant lesions and persistent genital infections. However, these trials were designed before the etiologic relationship between HPV and OPC was established. There are differences in the epidemiology of oral and genital HPV infection, such as differences in age and sex distributions, which suggest that the vaccine efficacy observed in genital cancers may not be directly translatable to the cancers of the oropharynx. Evaluation of vaccine efficacy is challenging in the oropharynx because no premalignant lesion analogous to cervical intraepithelial neoplasia in cervical cancer has yet been identified. To truly investigate the efficacy of these vaccines in the oropharynx, additional clinical trials with feasible endpoints are needed. Cancer 2016;122:2313-2323. © 2016 American Cancer Society.

Objectives/Hypothesis To describe the impact of a mentored clerkship initiative on underrepresented minority medical students interested in otolaryngology–head and neck surgery (OHNS). Study Design Prospective observational study. Methods An outreach effort to recruit underrepresented minority students was initiated in 2008, consisting of either a 3‐month research clerkship or a 1‐month clinical rotation. Financial assistance and faculty mentorship was provided for students. Upon conclusion of the clerkship, students completed a post‐clerkship evaluation form. Students were followed regarding residency applications, match status, and publications. Evaluations were compiled and analyzed. The number of publications resulting from interaction with faculty mentors was calculated. Results Fifteen students participated in the clerkship from 11 medical schools. Of those, 10 students participated in the clinical clerkship, four in the research clerkship, and one in both clerkships. Evaluation (5‐point Likert scale) average scores and comments revealed high student satisfaction with the rotations (4.85), provided individual mentorship (4.85), and provided exposure to academic medicine (4.92). Participants indicated the rotation favorably impacted their decision to apply for OHNS residency training and increased their interest in academic medicine. The participants had an average number of 1.7 publications, with 1.18 publications in OHNS journals. Six publications resulted from direct interaction between students and faculty during the clerkship. Seven students applied for OHNS residency programs, and six matched successfully. Conclusion Mentored clerkships for underrepresented minority medical students increases interest in applying to OHNS residency training programs and is a successful approach to increasing physician diversity. It provides a pathway to expand research opportunities and increase student interest in academic medicine. Level of Evidence NA Laryngoscope , 126:2684–2688, 2016

The purpose of this study was to evaluate the influence of sex and race/ethnicity upon prevalence trends of human papillomavirus (HPV) in oropharyngeal cancer (OPC) and survival after OPC.This was a cohort study of patients included in the United States National Cancer Database who had been diagnosed with OPC between 2010 and 2015. Outcomes were HPV status of tumor specimens and overall survival. Sex- and race-stratified trends in HPV prevalence were estimated using generalized linear modeling. The influence of sex, race, and HPV tumor status on overall survival was compared by Kaplan-Meier method and Cox Proportional Hazards models.This analysis included 20,886 HPV-positive and 10,364 HPV-negative OPC patients. The prevalence of HPV-positive tumors was higher among men (70.6%) than women (56.3%) and increased significantly over time at a rate of 3.5% and 3.2% per year among men and women, respectively. The prevalence of HPV-positive tumors was highest among whites (70.2%), followed by Hispanics (61.3%), Asians (55.8%), and blacks (46.3%). Blacks and Hispanics experienced significantly more rapid increases in prevalence of HPV-positive tumors over time compared with whites (6.5% vs 5.6% vs 3.2% per year, respectively). In HPV-positive OPC, neither sex nor race/ethnicity was associated with survival among patients with HPV-positive OPC. In contrast, for HPV-negative OPC, risk of death was significantly higher for women versus men (adjusted hazard ratio [aHR], 1.17; 95% confidence interval [CI], 1.08-1.26) and blacks versus whites (aHR, 1.21; 95% CI, 1.10-1.33).The prevalence of HPV-positive tumors is increasing for all sex and race/ethnicity groups in the United States. Sex and race are independently associated with survival for HPV-negative but not HPV-positive OPC.

Abstract Background In the era of deintensification, little data are available regarding patients’ treatment preferences. The current study evaluated treatment‐related priorities, concerns, and regret among patients with head and neck squamous cell cancer (HNSCC). Methods A total of 150 patients with HNSCC ranked the importance of 10 nononcologic treatment goals relative to the oncologic goals of cure and survival. The level of concern regarding 11 issues and decision regret was recorded. Median rank was reported overall, and factors associated with odds of rank as a top 3 priority were modeled using logistic regression. Results Among the treatment effects analyzed, the odds of being a top 3 priority was especially high for cure (odds, 9.17; 95% confidence interval [95% CI], 5.05‐16.63), followed by survival and swallow (odds, 1.26 [95% CI, 0.88‐1.80] and odds, 0.85 [95% CI, 0.59‐1.21], respectively). Prioritization of cure, survival, and swallow was similar based on human papillomavirus (HPV) tumor status. By increasing decade of age, older participants were found to be significantly less likely than younger individuals to prioritize survival (odds ratio, 0.72; 95% CI, 0.52‐1.00). Concerns regarding mortality ( P = .04) and transmission of HPV to the patient’s spouse ( P = .03) were more frequent among participants with HPV‐associated HNSCC. Regret increased with additional treatment modalities ( P = .02). Conclusions Patients with HNSCC overwhelming prioritize cure, followed by survival and swallow. The decreased prioritization of survival by older age supports further examination of treatment preference by age. The precedence of oncologic over nononcologic priorities among patients regardless of HPV tumor status supports the conservative adoption of deintensification regimens until the interplay between competing oncologic and nononcologic treatment goals is better understood.

Case-control studies from the early 2000s demonstrated that human papillomavirus-related oropharyngeal cancer (HPV-OPC) is a distinct entity associated with number of oral sex partners. Using contemporary data, we investigated novel risk factors (sexual debut behaviors, exposure intensity, and relationship dynamics) and serological markers on odds of HPV-OPC.HPV-OPC patients and frequency-matched controls were enrolled in a multicenter study from 2013 to 2018. Participants completed a behavioral survey. Characteristics were compared using a chi-square test for categorical variables and a t test for continuous variables. Adjusted odds ratios (aOR) were calculated using logistic regression.A total of 163 HPV-OPC patients and 345 controls were included. Lifetime number of oral sex partners was associated with significantly increased odds of HPV-OPC (>10 partners: odds ratio [OR], 4.3 [95% CI, 2.8-6.7]). After adjustment for number of oral sex partners and smoking, younger age at first oral sex (<18 vs >20 years: aOR, 1.8 [95% CI, 1.1-3.2]) and oral sex intensity (>5 sex-years: aOR, 2.8 [95% CI, 1.1-7.5]) remained associated with significantly increased odds of HPV-OPC. Type of sexual partner such as older partners when a case was younger (OR, 1.7 [95% CI, 1.1-2.6]) or having a partner who had extramarital sex (OR, 1.6 [95% CI, 1.1-2.4]) was associated with HPV-OPC. Seropositivity for antibodies to HPV16 E6 (OR, 286 [95% CI, 122-670]) and any HPV16 E protein (E1, E2, E6, E7; OR, 163 [95% CI, 70-378]) was associated with increased odds of HPV-OPC.Number of oral sex partners remains a strong risk factor for HPV-OPC; however, timing and intensity of oral sex are novel independent risk factors. These behaviors suggest additional nuances of how and why some individuals develop HPV-OPC.

Importance Evidence is lacking from randomized clinical trials of hypoglossal nerve stimulation in obstructive sleep apnea (OSA). Objective To evaluate the safety and effectiveness of targeted hypoglossal nerve stimulation (THN) of the proximal hypoglossal nerve in patients with OSA. Design, Setting, and Participants This randomized clinical trial (THN3) was conducted at 20 centers and included 138 patients with moderate to severe OSA with an apnea-hypopnea index (AHI) of 20 to 65 events per hour and body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or less. The trial was conducted from May 2015 through June 2018. Data were analyzed from January 2022 through January 2023. Intervention Implant with THN system; randomized 2:1 to activation at month 1 (treatment) or month 4 (control). All received 11 months of THN with follow-up at months 12 and 15, respectively. Main Outcomes and Measures Primary effectiveness end points comprised AHI and oxygen desaturation index (ODI) responder rates (RRs). Treatment responses at months 4 and 12/15 were defined as a 50% or greater reduction in AHI to 20 or less per hour and an ODI decrease of 25% or greater. Coprimary end points comprised (1) month 4 AHI and ODI RR in the treatment greater than the control group and (2) month 12/15 AHI and ODI RR in the entire cohort exceeding 50%. Secondary end points included sleep apnea severity (AHI and ODI) and patient-reported outcomes (Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale). Results Among 138 participants, the mean (SD) age was 56 (9) years, and 19 (13.8%) were women. Month 4 THN RRs were substantially greater in those in the treatment vs control group (AHI, 52.3% vs 19.6%; ODI, 62.5% vs 41.3%, respectively) with treatment-control standardized mean differences of 0.725 (95% CI, 0.360-1.163) and 0.434 (95% CI, 0.070-0.843) for AHI and ODI RRs, respectively. Months 12/15 RRs were 42.5% and 60.4% for AHI and ODI, respectively. Improvements in AHI, ODI, Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, and EQ-5D visual analog scale scores were all clinically meaningful (medium to large effect size). Two serious adverse events and 100 nonserious related adverse events were observed from the implant procedure or study protocol. Conclusions and Relevance This randomized clinical trial found that THN demonstrated improvements in sleep apnea, sleepiness, and quality of life in patients with OSAs over an extended AHI and body mass index range without prior knowledge of pharyngeal collapse pattern. Clinically meaningful improvements in AHI and patient-reported responses compared favorably with those of distal hypoglossal nerve stimulation trials, although clinically meaningful differences were not definitive for ODI. Trial Registration ClinicalTrials.gov Identifier: NCT02263859

Management of the N0 neck in head and neck squamous cell carcinoma is an important issue for the head and neck surgeon. Experience with radionuclide-labeled colloid injection to identify a sentinel node in malignant melanoma suggests a high level of accuracy for this approach to identify microscopic metastasis when present. We set out to explore the feasibility of using the handheld gamma probe to identify radiolabeled sentinel nodes in oral squamous cell carcinoma.Five individuals with N0 necks and accessible oral or oropharyngeal primary sites from a major tertiary referral center.Radiolabel with unfiltered technetium Tc 99m sulfur colloid was injected in quadrants around the primary site followed by immediate dynamic lymphoscintigraphy. Open biopsy of the sentinel node was accomplished within 2 hours of injection after extirpation of the primary site. Regional or complete neck dissection was performed after sentinel node biopsy.Sentinel node biopsy accurately identified one or several nodes in 2 cases, including nodes containing metastatic cancer in 1. In the other 3 cases, the radiolabel failed to identify the sentinel node despite the presence of metastatic disease in the nodes at final pathologic study in 2.Detection and biopsy of the sentinel node are feasible for selected patients with oral head and neck squamous cell carcinoma with N0 necks. There is a potential savings of time, cost, and morbidity with this approach. However, several substantial problems were encountered with the technique in this limited series of patients. Establishing the reliability of lymphoscintigraphy in this setting would require testing in a much larger patient cohort. Our experience suggests that such an investment may not be warranted.

Esthesioneuroblastoma (ENB) is an uncommon malignant neoplasm of the upper nasal cavity. Therapeutic management approaches for this neoplasm lack uniformity and there is no universally accepted staging system.A retrospective review of 27 patients with histologically confirmed ENB managed at The Johns Hopkins Hospital.Eighty-five percent of patients had surgical resection as part of their disease management. Complete surgical resection was achieved in 62% of patients who had a craniofacial resection. Eighty percent of patients with negative surgical margins remain with no evidence of disease, with a median follow-up of 5.6 years. Adjuvant radiation therapy was beneficial to 62% of patients with positive surgical margins. Clinical responses were observed with cisplatin- and etoposide-containing chemotherapy regimens in patients with advanced disease. A revised staging system based on our experience is proposed.ENB is best managed by craniofacial resection with complete tumor resection. Adjuvant radiation therapy is warranted in patients that remain with positive histologic margins of resection. Chemotherapy with cisplatin- and etoposide-containing regimens may be useful for palliation of advanced disease.

Abstract Intraoperative electrophysiologic monitoring of the recurrent laryngeal nerve was performed with a commercially available device consisting of an endotracheal tube with integrated stainless‐steel‐wire surface EMG electrodes positioned at the level of the true vocal cords. Forty‐two recurrent laryngeal nerves were successfully monitored with this system in 31 patients undergoing thyroidectomy or parathyroidectomy. In all cases, evoked EMG responses were elicited by direct electrical recurrent laryngeal nerve stimulation. Stimulus thresholds for evoked responses ranged from 0.2 to 0.6 mA (mean 0.3 mA) for the 37 nerves with preoperative ipsilateral normal vocal cord mobility. Mechanically evoked potentials with acoustic signals were also detected during the surgical procedures related to recurrent laryngeal nerve manipulation. It may be concluded that surface electrode monitoring of the recurrent laryngeal nerve with this system provides a simplified, noninvasive technique that is as sensitive as monitoring with intramuscular laryngeal electrodes.

Contraction of the genioglossus (GG) has been shown to improve upper airway patency. In the present study, we evaluated responses in upper airway pressure-flow relationships during sleep to electrical stimulation (ES) of the GG in patients with obstructive sleep apnea. Five patients with chronically implanted hypoglossal nerve (HG) electrodes and nine patients with fine-wire electrodes inserted into the GG were studied. Airflow was measured at multiple levels of nasal pressure, and upper airway collapsibility was defined by the nasal pressure below which airflow ceased ["critical" pressure (Pcrit)]. ES shifted the pressure-flow relationships toward higher flow levels in all patients over the entire range of nasal pressure applied. Pcrit decreased similarly during both HG-ES and GG-ES (deltaPcrit was 3.98 +/- 2.31 and 3.18 +/- 1.70 cmH2O, respectively) without a significant change in upstream resistance. The site of collapse (velo- vs. oropharynx) did not influence the response to GG-ES. Moreover, ES-induced reductions in the apnea-hypopnea index of the HG-ES patients were associated with substantial decreases in Pcrit. Our findings imply that responses in apnea severity to HG-ES can be predicted by characterizing the patient's baseline pressure-flow relationships and response to GG-ES.

To demonstrate an oncologic basis for the recommendation to perform bilateral tonsillectomy as a routine measure in the search for a primary mucosal lesion in patients presenting with cervical nodal metastasis of squamous cell carcinoma (SCC).A case series of individuals selected from a 3-year period is reported.Academic medical center.Each individual presented with metastatic squamous cell carcinoma in a cervical lymph node from an unknown primary source. In each case, the primary source was identified in a tonsillectomy specimen, either located contralateral to the node, or in both tonsils.The rate of contralateral spread of metastatic cancer from occult tonsil lesions appears to approach 10%. For this reason, bilateral tonsillectomy is recommended as a routine step in the search for the occult primary in patients presenting with cervical metastasis of SCC and palatine tonsils intact.

Background: Cancer is caused by the accumulation of mutations that activate proto-oncogenes and inactivate tumor suppressor genes. The result is a clonal expansion of genetically identical daughter cells that eventually become clinical malignancies. The specific mutations acquired by the progenitor cell are like a fingerprint carried by each cell of the tumor. These mutations can serve as very specific markers for the presence of tumor cells in a background of normal cells. Methods: Mutations in the p53 gene recovered from head and neck squamous cell carcinomas were sequenced, and these altered DNA sequences were used retrospectively as tumor-specific genetic markers for cancer cells in the patient's saliva. Cloned p53 sequences amplified by the polymerase chain reaction from DNA extracted from banked preoperative saliva specimens were screened for the presence of tumor-specific mutations using radiolabeled oligonucleotide probes. Results: We identified tumor-specific mutations in preoperative saliva samples of 5 of the 7 patients evaluated (71%). Conclusions: These results suggest a potential for clinical applications of this novel approach to cancer detection using gene mutations as molecular markers for carcinomas. Cancer is caused by the accumulation of mutations that activate proto-oncogenes and inactivate tumor suppressor genes. The result is a clonal expansion of genetically identical daughter cells that eventually become clinical malignancies. The specific mutations acquired by the progenitor cell are like a fingerprint carried by each cell of the tumor. These mutations can serve as very specific markers for the presence of tumor cells in a background of normal cells. Mutations in the p53 gene recovered from head and neck squamous cell carcinomas were sequenced, and these altered DNA sequences were used retrospectively as tumor-specific genetic markers for cancer cells in the patient's saliva. Cloned p53 sequences amplified by the polymerase chain reaction from DNA extracted from banked preoperative saliva specimens were screened for the presence of tumor-specific mutations using radiolabeled oligonucleotide probes. We identified tumor-specific mutations in preoperative saliva samples of 5 of the 7 patients evaluated (71%). These results suggest a potential for clinical applications of this novel approach to cancer detection using gene mutations as molecular markers for carcinomas.

Abstract Objective : To determine factors including treatment modalities which influence survival in patients with osteosarcoma of the head and neck. Study Design : Retrospective clinicopathologic study of 27 patients with osteosarcoma of the head and neck. Methods : The clinical charts and pathology slides were reviewed on 27 patients who had osteosarcoma of the head and neck between 1946 and 1998. The following variables were examined for their effect on survival: age of diagnosis, site of tumor, presentation, race, sex, prior radiation exposure, retinoblastoma history, margin status, and method of treatment. Results : The average age at the time of diagnosis of the patients was 37.6 years (range, 7–82 y). The sex distribution was similar with 14 male and 13 female patients. Eight of 27 patients had osteosarcoma of the mandible, 9 of 27 had osteosarcoma of the maxilla and paranasal sinuses, and in 10 of 27 patients osteosarcoma occurred elsewhere, including the temporal bones, occipital bones, and orbit. The overall 2‐year survival was 66% with a 5‐year survival rate of 55%. Conclusions : Positive surgical margins and a high tumor grade were found to have a statistically deleterious effect on overall survival. There was no detectable effect on survival of age, race, sex, prior radiation exposure, tumor site, and tumor cell type. It was not possible to differentiate between the different adjuvant treatment modalities because of the small numbers in the study. Key Words : Bone, malignancy, osteogenic sarcoma, radiation therapy, surgery.

To determine if preoperative radiographic cross-sectional images can predict the nerve of origin of a parapharyngeal schwannoma and, specifically, whether it originates from the vagus nerve or the cervical sympathetic chain.A retrospective review.Academic medical center.The study population comprised 12 patients who underwent surgical resection of schwannomas of the parapharyngeal space. The nerve of origin was identified based on operative findings and postoperative physical examinations. Of the 12 patients, 11 underwent preoperative magnetic resonance imaging and 1 underwent preoperative contrast-enhanced computed tomography. A CAQ (Certificate of Added Qualification)-certified neuroradiologist reviewed the imaging studies, blinded to the surgically determined nerve of origin. For each case, it was predicted whether the tumor arose from the vagus nerve or sympathetic chain based on the location of the schwannoma with reference to the carotid sheath vessels.Identification of the nerves of origin using the displacement of vessels as a marker.At the time of operation, it was determined that 5 patients (42%) had schwannomas from the cervical sympathetic chain and 7 patients (58%) had schwannomas of the cervical vagus nerve. By imaging, the nerve of origin was successfully determined in 4 of 5 cases of sympathetic chain schwannoma (80%) and in 7 of 7 cases of vagal nerve schwannoma (100%). Schwannomas of the cervical sympathetic chain were found to displace both the carotid and jugular vessels without separating them. Vagal nerve schwannomas were found to separate the carotid arteries from the internal jugular vein. A vagal nerve schwannoma may also displace the sheath vessels posteriorly, without splaying them.Carotid and jugular vessel displacement, as determined by cross-sectional imaging, can predict the likely nerve of origin of a parapharyngeal space schwannoma. This determination allows for effective preoperative counseling regarding the expected sequelae of surgical resection.

Abstract Warthin's tumor previously has been thought to occur much more commonly in men than in women and rarely in African Americans. One hundred thirty‐two cases of Warthin's tumor treated at The Johns Hopkins Hospital from 1952 to 1992 were retrospectively reviewed. There were 90 (68%) men and 42 (32%) women, with an overall man‐to‐woman ratio of 2.2:1. The number and percentage of women with Warthin's tumor increased over each consecutive decade: 1952 to 1962, 5 (21%); 1963 to 1972, 6 (29%); 1973 to 1982, 11 (31%); and 1983 to 1992, 20 (39%). A positive smoking history was found in 88% of the men and in 89% of the women with a Warthin's tumor. Eleven (8%) African Americans and 1 (0.75%) Asian American were diagnosed to have a Warthin's tumor. Also, the incidence of African Americans with a Warthin's tumor increased over each decade: 0 (0%), 1 (4.8%), 2 (5.5%), and 8 (16%). This study's results indicate a progressive increase in the occurrence of this tumor in women and in African Americans and a higher overall incidence in African Americans than previously reported.

•<i>Objective</i>.—To evaluate the complications of anterior craniofacial resection and correlate their impact with tumor control status. <i>Design</i>.—We conducted a retrospective review of 32 consecutive, operable patients' records seen over a 6-year period, requiring 35 procedures. <i>Setting</i>.—Academic tertiary referral medical center. <i>Participants</i>.—Twenty-six patients (81%) had malignant lesions (esthesioneuroblastoma, squamous cell carcinoma, and a group of miscellaneous malignant tumors). Six patients had various benign neoplasms. <i>Intervention</i>.—The surgical approach involved bifrontal craniotomy coupled with lateral rhinotomy in 19 cases (61%), facial degloving in 10 cases (32%), a total rhinectomy in one case, and endoscopic sinusectomy without facial incision in two cases. <i>Outcome Measure</i>.—Clinically noted complications and oncologic outcome. <i>Results</i>.—There was one avoidable perioperative death indirectly associated with the patient's procedure. Nine patients suffered significant intracranial neurological complications such as tension pneumocephalus and delayed epidural abscess. All of these complications were managed successfully. Of patients with malignant tumors, 13 (52%) are alive with no evidence of disease and one is alive with recurrence after a mean follow-up period of 28.9 months. The 10 patients who succumbed to disease had a mean postoperative survival of 22.9 months. <i>Conclusions</i>.—In contrast to the perspective of only a decade ago, we conclude that craniofacial resection is a relatively safe, versatile, and effective procedure for surgical management of tumors involving the anterior skull base. (<i>Arch Otolaryngol Head Neck Surg</i>. 1992;118:913-917)

A second review of histopathologic diagnoses is a quality assurance practice that helps expose diagnostic errors and guide management of patients being referred from outside hospitals. Identification of anatomic regions and specimen types that are prone to diagnostic error will be helpful in guiding policy decisions regarding mandatory second opinion surgical pathology.All available outside pathology reports were retrieved for patients referred to The Johns Hopkins Hospital Department of Otolaryngology-Head and Neck Surgery between January 1, 1990, and January 1, 2000. The outside diagnosis was compared with diagnosis rendered at the referral hospital. A discrepant diagnosis was regarded as any change resulting in a significant modification in therapy or prognosis.Of the 814 cases reviewed, the second opinion surgical pathology diagnosis resulted in 54 (7%) changed diagnoses. Of the changed diagnosis, 13 (24%) involved a change from a benign to a malignant diagnosis; 8 (15%) involved a change from a malignant to a benign diagnosis; and 33 (61%) involved a change in tumor classification. Follow-up information supported the second opinion diagnosis in 41 of 43 cases (95%).In a consequential number of cases, second opinion surgical pathology results in major therapeutic and prognostic modifications for patients sent to large referral hospitals for head and neck oncologic surgery.

Purpose: To determine factors predictive of local-regional recurrence (LRR) after surgery alone for carcinomas of the major salivary glands in an attempt to evaluate the potential role of postoperative radiation therapy. Methods and Materials: Between 1960 and 2004, 207 patients with carcinomas of the major salivary glands were treated with definitive surgery without postoperative radiation therapy. Histology was: 67 mucoepidermoid (32%), 50 adenoid cystic (24%), 34 acinic cell (16%), 23 malignant mixed (11%), 16 adenocarcinoma (8%), 6 oncocytic (3%), 6 myoepithelial (3%), and 5 other (2%). Distribution of pathologic T-stage was: 54 T1 (26%), 83 T2 (40%), 46 T3 (22%), and 24 T4 (12%). Sixty patients (29%) had microscopically positive margins. Median follow-up was 6.1 years (range, 0.5–18.7 years). Results: The 5-year and 10-year estimates of local-regional control were 86% and 74%, respectively. A Cox proportional hazard model identified pathologic lymph node metastasis (hazard ratio [HR], 4.8; p = 0.001), high histologic grade (HR, 4.2; p = 0.003), positive margins (HR, 2.6; p = 0.03), and T3–4 disease (HR, 2.0; p = 0.04) as independent predictors of LRR. The presence of any one of these factors was associated with 10-year local-regional control rates of 37% to 63%. Conclusion: Lymph node metastasis, high tumor grade, positive margins, and T3–4 stage predict for significant rates of LRR after surgery for carcinomas of the major salivary glands. Postoperative radiation therapy should be considered for patients with these disease characteristics. Purpose: To determine factors predictive of local-regional recurrence (LRR) after surgery alone for carcinomas of the major salivary glands in an attempt to evaluate the potential role of postoperative radiation therapy. Methods and Materials: Between 1960 and 2004, 207 patients with carcinomas of the major salivary glands were treated with definitive surgery without postoperative radiation therapy. Histology was: 67 mucoepidermoid (32%), 50 adenoid cystic (24%), 34 acinic cell (16%), 23 malignant mixed (11%), 16 adenocarcinoma (8%), 6 oncocytic (3%), 6 myoepithelial (3%), and 5 other (2%). Distribution of pathologic T-stage was: 54 T1 (26%), 83 T2 (40%), 46 T3 (22%), and 24 T4 (12%). Sixty patients (29%) had microscopically positive margins. Median follow-up was 6.1 years (range, 0.5–18.7 years). Results: The 5-year and 10-year estimates of local-regional control were 86% and 74%, respectively. A Cox proportional hazard model identified pathologic lymph node metastasis (hazard ratio [HR], 4.8; p = 0.001), high histologic grade (HR, 4.2; p = 0.003), positive margins (HR, 2.6; p = 0.03), and T3–4 disease (HR, 2.0; p = 0.04) as independent predictors of LRR. The presence of any one of these factors was associated with 10-year local-regional control rates of 37% to 63%. Conclusion: Lymph node metastasis, high tumor grade, positive margins, and T3–4 stage predict for significant rates of LRR after surgery for carcinomas of the major salivary glands. Postoperative radiation therapy should be considered for patients with these disease characteristics.

Few reports have described in detail the injuries that occur to the oral cavity, pharynx, and larynx following caustic ingestion. The role of dynamic radiographic studies to delineate the extent of damage has been minimized. In-depth radiographic analysis of such cases has not, to our knowledge, been previously reported. In order to examine the injuries and functional abnormalities of these sites following caustic ingestion, the records of The Johns Hopkins Swallowing Center were reviewed. Five patients were identified as having significant upper aerodigestive tract caustic injuries. All patients had dysphagia, epiglottis injuries, and incomplete laryngeal protection with aspiration. Four of five had sustained some degree of esophageal stenosis. Also noted were pharyngeal muscle dysfunction, nasopharyngeal regurgitation, tongue fixation, and hypopharyngeal stenosis. Roentgenographic findings are described and illustrated. The multidisciplinary approach to the management and rehabilitation of these patients is discussed.

Upper airway occlusion in obstructive sleep apnea has been attributed to a decline in pharyngeal neuromuscular activity occurring in a structurally narrowed airway. Surgical treatment focuses on the correction of anatomic abnormalities, but there is a potential role for activation of the upper airway musculature, especially with stimulation of the hypoglossal nerve and genioglossus muscle. We present evidence from research on upper airway neuromuscular electrical stimulation in animals and humans. We also present results from eight obstructive sleep apnea patients with a fully implanted system for hypoglossal nerve stimulation, demonstrating an improvement in upper airway collapsibility and obstructive sleep apnea severity. Future research, including optimization of device features and stimulation parameters as well as patient selection, is necessary to make hypoglossal nerve stimulation a viable alternative to positive airway pressure therapy and upper airway surgical procedures.

To evaluate the incidence of nodal relapses from carcinomas of the salivary glands among patients with clinically negative necks in an attempt to determine the potential utility of elective neck irradiation (ENI).Between 1960 and 2004, 251 patients with clinically N0 carcinomas of the salivary glands were treated with surgery and postoperative radiation therapy. None of the patients had undergone previous neck dissection. Histology was: adenoid cystic (84 patients), mucoepidermoid (60 patients), adenocarcinoma (58 patients), acinic cell (21 patients), undifferentiated (11 patients), carcinoma ex pleomorphic adenoma (7 patients), squamous cell (7 patients), and salivary duct carcinoma (3 patients); 131 patients (52%) had ENI. Median follow-up was 62 months (range, 3-267 months).The 5- and 10-year actuarial estimates of nodal relapse were 11% and 13%, respectively. The 10-year actuarial rates of nodal failure were 7%, 5%, 12%, and 16%, for patients with T1, T2, T3, and T4 disease, respectively (p = 0.11). The use of ENI reduced the 10-year nodal failure rate from 26% to 0% (p = 0.0001). The highest crude rates of nodal relapse among those treated without ENI were found in patients with squamous cell carcinoma (67%), undifferentiated carcinoma (50%), adenocarcinoma (34%), and mucoepidermoid carcinoma (29%). There were no nodal failures observed among patients with adenoid cystic or acinic cell histology.ENI effectively prevents nodal relapses and should be used for select patients at high risk for regional failure.

To assess the risk factor of capsular rupture for individual prognosis and potential therapeutic decision making, the present meta-analysis elaborated the prognostic significance of perinodal spread in a large group of patients suffering from head and neck squamous cell carcinomas (HNSCC). A review of the published literature was conducted, and fixed and random effects models were applied for estimation of the summarised odds ratio and 95% confidence intervals, including a test for homogeneity of the odds ratios. Study methodology allowed the enrollment of only nine studies of 115 published papers. Excluded studies lacked regarding primary tumour location, number and location of lymph node metastases, values on five-year survival, or adequate follow-up data. A summarised odds ratio of 2.7 leads to the conclusion that perinodal spread negatively impacts the five-year survival. The lower confidence limit of more than 2 also supports the concept that perinodal spread significantly reduces (doubled risk) the five-year-survival. These results support the conclusion that perinodal spread is a significant adverse risk factor for survival in patients with HNSCC.

Adenoid cystic carcinoma (ACC) is the second most common malignant neoplasm of the salivary glands. Most patients survive more than 5 years after surgery and postoperative radiation therapy. The 10 year survival rate, however, drops to 40%, due to locoregional recurrences and distant metastases. Improving long-term survival in ACC requires the development of more effective systemic therapies based on a better understanding of the biologic behavior of ACC. Much preclinical research in this field involves the use of cultured cells and, to date, several ACC cell lines have been established. Authentication of these cell lines, however, has not been reported. We performed DNA fingerprint analysis on six ACC cell lines using short tandem repeat (STR) examinations and found that all six cell lines had been contaminated with other cells. ACC2, ACC3, and ACCM were determined to be cervical cancer cells (HeLa cells), whereas the ACCS cell line was composed of T24 urinary bladder cancer cells. ACCNS and CAC2 cells were contaminated with cells derived from non-human mammalian species: the cells labeled ACCNS were mouse cells and the CAC2 cells were rat cells. These observations suggest that future studies using ACC cell lines should include cell line authentication to avoid the use of contaminated or non-human cells.

Sialendoscopy and sialoMRI enables diagnosis of salivary gland obstructive pathologies, such as lithiasis, stenosis, and dilatations. Therefore, a classification of these pathologies is needed, allowing large series comparisons, for better diagnosis and treatment of salivary pathologies.With help from people from the European Sialendoscopy Training Center (ESTC), the results of sialographies, sialoMRI and sialendoscopies, a comprehensive classification of obstructive salivary pathologies is described, based on the absence or presence of lithiasis (L), stenosis (S), and dilatation (D) ("LSD" classification).It appears that a classification of salivary gland obstructive pathologies should be described. We hope it will be widely used and of course criticized to be improved and to compare the results of salivary gland diagnostic methods, such as sialography and sialendoscopy, and also the results and indications for salivary gland therapeutic methods, such as lithotripsy, sialendoscopy, and/or open surgery.

Objectives The purpose of this study was to investigate etiologic factors for sialolithiasis in a population of patients from the United States. Study Design Retrospective, cohort study. Setting Tertiary university. Materials and Methods Charts for all patients diagnosed with sialolithiasis between January 2001 and February 2010 were retrospectively reviewed. Demographic factors, smoking history, comorbid medical conditions, and medication history were recorded. Statistical analyses were then performed on the collected data. Population prevalences of smoking, diuretic usage, cholelithiasis, and nephrolithiasis were obtained through literature review. Results A total of 153 patients with sialolithiasis were identified. Of these patients, 125 (82%) had submandibular sialolithiasis, and 28 (18%) had parotid sialolithiasis. Positive smoking histories were present in 67 individuals (44%). Both the current rate of smoking and the rate of a history of smoking were higher in our cohort when compared with the general population, although the differences did not reach statistical significance. Smoking history did not correlate with the size of the primary sialolith. Diuretic usage in the cohort was observed at a rate of 20%, higher than reported population rates of diuretic use of 8.7%. The prevalences of cholelithiasis and nephrolithiasis were not different from observed population rates. Conclusions Sialolithiasis is an uncommon condition of unclear etiology. This study represents an initial attempt to quantify the prevalence of smoking and diuretic therapy in a population of patients with sialolithiasis.

HPV-positive oropharyngeal cancer (OPC) patients have been observed to be younger than patients with HPV-negative OPC at diagnosis. We evaluated recent trends in age at OPC diagnosis, and whether older age attenuates the survival benefit of HPV-positive tumor status. Patients diagnosed with OPC from 2004 to 2014 represented in the National Cancer Database were included. HPV tumor status was available after 2010. Trends in age by calendar year were compared using linear regression. Overall survival was compared using Cox Proportional Hazards models. The mean age of OPC patients (N = 119,611) increased significantly from 2004 to 2014 (ß = 0.21 years of age per calendar year, 95% confidence interval [CI] = 0.19–0.23). The increase in age from 2010 to 2014 was similar for HPV-positive (N = 21,880; ß = 0.63, 95%CI = 0.53–0.72) and HPV-negative (N = 11,504; ß = 0.59, 95%CI = 0.45–0.74) patients. Between 2010 and 2014, the proportion of OPCs that were HPV-positive increased significantly for all age groups, including for patients ≥70 years old (from 45% to 60%, ptrend < 0.001). Although patients ≥70 years with HPV-OPC had improved survival compared to those with HPV-negative OPC (adjusted hazard ratio [aHR] = 0.65, 95%CI = 0.55–0.76), the survival benefit of HPV-positive tumor status was significantly attenuated compared to younger HPV-OPC patients (50–59 years: aHR = 0.45, 95%CI = 0.39–0.51; pinteraction < 0.001). The age at OPC diagnosis is increasing for both HPV-positive and HPV-negative patients, and a rising proportion of older patients have HPV-positive tumors. These findings dispel the notion that HPV-positive OPC is a disease of younger patients, identify a growing elderly population of HPV-positive OPC patients with reduced survival, and have implications for evolving treatment paradigms.

ABSTRACT Objective To review recent literature on human papillomavirus‐related (HPV‐positive) oropharyngeal squamous cell carcinoma (OPC) and focus on implications of recurrent and metastatic disease. Methods Primary articles from 1990 to 2016 indexed in MEDLINE (1) pertaining to the epidemiology of HPV‐positive OPC and (2) providing clinical insight into recurrent and metastatic OPC. Results The incidence of HPV‐positive OPC is increasing globally. HPV‐positive OPC is a subtype with distinct molecular and clinical features including enhanced treatment response and improved overall survival. While disease recurrence is less common in patients with HPV‐positive OPC, up to 36% of patients experience treatment failure within eight years. Recurrent and metastatic OPC has historically signified poor prognosis, however recent data are challenging this dogma. Here, we discuss recurrent and metastatic OPC in the context of HPV tumor status. Conclusion HPV‐positive OPC exhibits distinct genetic, cellular, epidemiological, and clinical features from HPV‐negative OPC. HPV tumor status is emerging as a marker indicative of improved prognosis after disease progression in both locoregionally recurrent and distant metastatic OPC. Level of Evidence N/A.

With an annual incidence of less than 1 per million, salivary gland malignancies in children are rare, constituting less than 10% of pediatric head and neck cancer. Although over 20 histologic types of salivary gland cancer have been reported in adults, a smaller number have been observed in the pediatric population. Mucoepidermoid carcinoma is the most common histologic type, followed by acinic cell carcinoma. Since the majority of salivary gland carcinomas are diagnosed at an early stage, the overall prognosis is often favorable with complete surgical resection. To date, no prospective or retrospective data comparing outcomes of surgery alone versus multimodality therapy in the management of salivary gland malignancies in the pediatric population exists. Consequently, management decisions are made on a case-by-base basis, taking prognosis, treatment-related morbidity, and long-term sequelae into account.

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; The discovery of mutations in epidermal growth factor receptor (EGFR) has dramatically changed the treatment of patients with non-small-cell lung cancer (NSCLC), the leading cause of cancer deaths worldwide. EGFR-targeted therapies show considerable promise, but drug resistance has become a substantial issue. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We reviewed the literature to provide an overview of the drug resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The mechanisms causing primary, acquired and persistent drug resistance to TKIs vary. Researchers and clinicians, who have used study findings to develop more effective therapeutic approaches, have found that the sequential use of single agents presents a formidable challenge, suggesting that multidrug combinations must be considered. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; In the era of precision medicine, oncologists should promptly obtain an accurate diagnosis of drug resistance in each patient to be able to design the most relevant combination therapy to overcome patient-specific drug resistance.

BACKGROUND Patients with human papillomavirus (HPV)‐related oropharyngeal cancer (OPC) have improved survival when compared with those with HPV‐negative OPC. Unfortunately, the American Joint Committee on Cancer seventh edition (AJCC‐7ed) staging system does not account for the prognostic advantage observed with HPV‐positive OPC. The purpose of the current study was to validate and compare 2 recently proposed staging systems for HPV‐positive OPC. METHODS Patients treated for HPV‐positive OPC from 2005 to 2015 at Johns Hopkins Hospital (JHH) were included for analysis. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON‐S) and The University of Texas MD Anderson Cancer Center (MDACC) staging systems were applied and survival was calculated using Kaplan‐Meier methods. Cox proportional hazard regression was used to determine the relationship between stage of disease and survival. Models were compared using the Akaike information criterion (AIC). RESULTS A total of 435 patients were eligible for analysis. There was a dramatic shift in lymph node category and overall stage of disease when ICON‐S and MDACC stage were applied to the JHH cohort. There was superior stratification of overall survival and progression‐free survival by ICON‐S stage. Both proposed models had an improved fit based on AIC scores ( P &lt;.001 for both) over the AJCC‐7ed. The ICON‐S staging system had the lowest AIC score, and thus a better fit within the JHH population. CONCLUSIONS The current analysis provides external validation for both staging systems in an independent and heterogeneously treated patient population. Although the MDACC staging system is an improvement over the AJCC‐7ed, the ICON‐S stage provides superior stratification of overall and progression‐free survival, thereby supporting its use as the updated AJCC staging system for OPC. Cancer 2017;123:1768–1777 . © 2017 American Cancer Society .

A volume-outcome association exists for larynx cancer surgery, but to date it has not been investigated for specific surgical procedures.To characterize the volume-outcome association specifically for laryngectomy surgery and to identify a minimum hospital volume threshold associated with improved outcomes.In this cross-sectional study, the Nationwide Inpatient Sample was used to identify 45 156 patients who underwent laryngectomy procedures for a malignant laryngeal or hypopharyngeal neoplasm between January 2001 and December 2011. The analysis was performed in 2018. Hospital laryngectomy volume was modeled as a categorical variable.Associations between hospital volume and in-hospital mortality, complications, length of hospitalization, and costs were examined using multivariate logistic regression analysis.Among 45 156 patients (mean age, 62.6 years; age range, 20-96 years; 80.2% male) at 5516 hospitals, higher-volume hospitals were more likely to be teaching hospitals in urban locations; were more likely to treat patients who had hypopharyngeal cancer, were of white race/ethnicity, were admitted electively, had no comorbidity, and had private insurance; and were more likely to perform flap reconstruction or concurrent neck dissection. After controlling for all other variables, hospitals treating more than 6 cases per year were associated with lower odds of surgical and medical complications, with a greater reduction in the odds of complications with increasing hospital volume. High-volume hospitals in the top-volume quintile (>28 cases per year) were associated with decreased odds of in-hospital mortality (odds ratio, 0.45; 95% CI, 0.23-0.88), postoperative surgical complications (odds ratio, 0.63; 95% CI, 0.50-0.79), and acute medical complications (odds ratio, 0.63; 95% CI, 0.48-0.81). A statistically meaningful negative association was observed between very high-volume hospital care and the mean incremental length of hospitalization (-3.7 days; 95% CI, -4.9 to -2.4 days) and hospital-related costs (-$4777; 95% CI, -$9463 to -$900).Laryngectomy outcomes appear to be associated with hospital volume, with reduced morbidity associated with a minimum hospital volume threshold and with reduced mortality, morbidity, length of hospitalization, and costs associated with higher hospital volume. These data support the concept of centralization of complex care at centers able to meet minimum volume thresholds to improve patient outcomes.

Preoperative fine needle aspiration (FNA) of parotid lesions often is used in the initial evaluation of parotid masses, but its role in guiding surgical decision making remains unclear, in part due to varying diagnostic accuracy reported. We sought to evaluate the role of preoperative FNA in detection of malignancy and impact on surgical management.Retrospective study.The medical records of patients who underwent parotidectomy at a single tertiary medical center were reviewed from 2000 to 2015. Patients who had a preoperative FNA comprised the study cohort.A total of 1,074 consecutive patients underwent parotidectomy during the study period; of those, 477 had a preoperative FNA. FNA was nondiagnostic in 26 cases. There were 29 false positives (6.4%), 26 false negatives (5.8%), 122 true positives (27.1%), and 274 true negatives (60.8%). The sensitivity and specificity of FNA were 82.4% and 90.4%, respectively, with a positive predictive value of 80.8% and a negative predictive value of 91.3%. The overall accuracy of preoperative FNA was 87.8%. The preoperative FNA resulted in a change in the surgical plan in 85 (18.9%) cases. In 66 of these cases (78%), surgery was extended to include neck dissection at time of resection. In 10 cases, FNA led to surgical management over surveillance. In 11 cases, FNA downgraded the extent of surgery planned to an excisional biopsy.Preoperative FNA is a valuable adjunct in the surgical management of parotid lesions, with high specificity for the detection of malignant disease.4. Laryngoscope, 128:398-402, 2018.

To evaluate the short- and long-term consequences of palliative reresection of specific symptomatic lesions in patients with widely disseminated (incurable) medullary thyroid cancer (MTC).Although reoperative neck microdissections can normalize calcitonin levels in patients with metastatic MTC confined to regional lymph nodes, there is no curative therapy for widely metastatic disease. However, these patients frequently have prolonged survival, but often with debilitating symptoms.Between October 1981 and January 1997, 16 patients (mean age, 46 +/- 3 years; 10/16 female) underwent 21 palliative reoperations for unresectable MTC at the Johns Hopkins Hospital. All patients had significant symptom(s) or impending compromise of vital structures by a discrete lesion and had unequivocal preoperative evidence of a total disease burden that was unresectable.The mean interval from initial thyroidectomy to palliative surgery was 5.8 +/- 1.5 years. All patients had significant tumor burdens as evidenced by preoperative calcitonin values ranging from 900 to 222,500 pg/mL (nL < or = 17 pg/mL). The palliative operations consisted of reoperative neck dissection/mass excision (11), mediastinal mass resection (4), esophagectomy (1), liver trisegmentectomy (1), sigmoidectomy (1), bilateral simple mastectomies (1), pituitary resection (1), and subcutaneous mass excisions (1). All but two of the operative specimens contained MTC. There was no perioperative mortality. The long-term morbidity rate was limited to one recurrent laryngeal nerve injury. All patients had initial relief of the index symptom(s) after the palliative surgery, followed by a median actuarial symptom-free survival rate of 8.2 years.Patients with widely metastatic MTC often live for years, but many develop symptoms secondary to tumor persistence or progression. Judicious palliative, reoperative resection of discrete, symptomatic lesions can provide significant long-term relief of symptoms with minimal operative mortality and morbidity. In selected patients with metastatic MTC lesions causing significant symptoms or physical compromise, palliative reoperative resection should be considered despite the presence of widespread incurable metastatic disease.

Abstract Objectives: Evaluate effectiveness of routine tonsillectomy in the assessment of patients with squamous cell carcinoma of the neck of unknown primary, and evaluate outcomes of this group compared with patients without a primary identified initially. Study Design: A retrospective review of the medical records of 37 patients presenting with an unknown primary tumor over a 10‐year period. Methods: Charts were reviewed for age and sex of patients, methods of evaluation and diagnosis, sites of tissues obtained on biopsy, N stage of disease, and presence of extracapsular spread. Recurrence and survival data were collected over a mean follow‐up period of 34 months. Results: All primary lesions discovered through pathologic evaluation arose from the tonsil (9/9), and all were detected in patients undergoing tonsillectomy in conjunction with direct laryngoscopy. None of the patients (0/9) with occult tonsillar carcinoma have had recurrence, in contrast to 60% (15/25) of remaining patients. Patients with tonsillar primary lesions demonstrated less extracapsular spread of disease (25%) than patients without tonsillar primaries (67%), despite similar N staging within the two groups. Conclusions: Occult tonsillar carcinoma accounts for the unknown primary more frequently than was previously recognized. Bilateral tonsillectomy is recommended to increase the detection yield and to capture the rare case of bilateral disease. A lower incidence of extracapsular spread and reduced recurrence rates in patients with unknown primary tumors presenting as occult tonsillar carcinoma may contribute to the improved prognosis observed in this group. Laryngoscope , 108:1605–1610, 1998

Fine needle aspiration is a safe diagnostic technique that is widely employed for lesions of the head and neck. Among head and neck sites, the parotid gland stands apart for the number, diversity and peculiarity of pathologic processes to target this structure. This matchless complexity has prompted a thoughtful discussion regarding the application of the fine needle aspiration to parotid masses--a discussion that has primarily focused on the reliability of the fine needle aspiration as a diagnostic tool, and on its utility in guiding patient management.Recent studies have confirmed a high overall accuracy rate for fine needle aspiration evaluation of parotid masses, ranging from 90 to 95%. At the same time, these soaring accuracy rates cannot be uniformly anticipated across all diagnostic scenarios. Fine needle aspiration is notoriously unreliable in recognizing the malignant nature of the parotid carcinoma, providing its precise classification, and establishing its grade. A few malignant neoplasms are particularly prone to diagnostic error. Acinic cell carcinoma is frequently interpreted as benign or even nonneoplastic; and low-grade lymphomas are often discounted as inflammatory processes.Parotid gland masses are not particularly conducive to diagnostic accuracy and precision by fine needle aspiration. Accordingly, indiscriminant reliance on the fine needle aspiration findings at the expense of the clinical, radiographic, and intraoperative findings is unwarranted. Whether one uses the fine needle aspiration routinely or selectively in patients with parotid masses, the fine needle aspiration findings should contribute to, not displace, the overall diagnostic impression.

Purpose: To review a single-institution experience with the management of salivary gland cancers treated by radiation alone.Methods and Materials: Between 1960 and 2004, 45 patients with newly diagnosed salivary gland carcinomas were treated with definitive radiation to a median dose of 66 Gy (range, 57–74 Gy). Distribution of T-stage was: 24% T1, 18% T2, 31% T3, and 27% T4. Histology was: 14 mucoepidermoid (31%), 10 adenocarcinoma (22%), 8 adenoid cystic (18%), 4 undifferentiated (9%), 4 acinic (9%), 2 malignant mixed (4%), 2 squamous (4%), and 1 salivary duct carcinoma (2%). No patient had clinical or pathologic evidence of lymph node disease. Median follow-up was 101 months (range, 3–285 months).Results: The 5-year and 10-year rate estimates of local control were 70% and 57%, respectively. A Cox proportional hazard model identified T3–4 disease (p = 0.004) and radiation dose lower than 66 Gy (p = 0.001) as independent predictors of local recurrence. The 10-year overall survival and distant metastasis–free rates were 46% and 67%, respectively.Conclusion: Radiation therapy alone is a reasonable alternative to surgery in the definitive management of salivary gland cancers and results in long-term survival in a significant proportion of patients. Radiation dose in excess of 66 Gy is recommended. Purpose: To review a single-institution experience with the management of salivary gland cancers treated by radiation alone. Methods and Materials: Between 1960 and 2004, 45 patients with newly diagnosed salivary gland carcinomas were treated with definitive radiation to a median dose of 66 Gy (range, 57–74 Gy). Distribution of T-stage was: 24% T1, 18% T2, 31% T3, and 27% T4. Histology was: 14 mucoepidermoid (31%), 10 adenocarcinoma (22%), 8 adenoid cystic (18%), 4 undifferentiated (9%), 4 acinic (9%), 2 malignant mixed (4%), 2 squamous (4%), and 1 salivary duct carcinoma (2%). No patient had clinical or pathologic evidence of lymph node disease. Median follow-up was 101 months (range, 3–285 months). Results: The 5-year and 10-year rate estimates of local control were 70% and 57%, respectively. A Cox proportional hazard model identified T3–4 disease (p = 0.004) and radiation dose lower than 66 Gy (p = 0.001) as independent predictors of local recurrence. The 10-year overall survival and distant metastasis–free rates were 46% and 67%, respectively. Conclusion: Radiation therapy alone is a reasonable alternative to surgery in the definitive management of salivary gland cancers and results in long-term survival in a significant proportion of patients. Radiation dose in excess of 66 Gy is recommended. IntroductionMalignant tumors of the salivary glands account for approximately 3% of all head-and-neck cancers (1Foote R.L. Olsen K.D. Bonner J.A. et al.Salivary gland cancer.in: Gunderson L.L. Tepper J.E. Clinical radiation oncology. Churchill Livingstone, Philadelphia2000: 518-534Google Scholar). While surgical excision forms the mainstay of treatment, a small proportion of newly diagnosed patients are either not candidates for definitive resection or undergo limited procedures leaving behind gross residual disease. Typically, these patients are deemed inoperable because of technical issues related to the extensiveness or location of the primary tumor. However, another subset of inoperable patients present with medical comorbidities that places them at unacceptably high risk for perioperative complications. Lastly, some patients refuse surgical therapy out of personal preference. Regardless of the underlying reasons, these inoperable patients have all traditionally been offered definitive radiation therapy as an alternative to surgery for the primary treatment of their salivary gland tumors. Although carcinomas originating from the salivary glands were once thought to be radioresistant with radiation alone reserved for palliation, it is becoming increasingly evident that cure may be possible in appropriately selected patients (2King J.J. Fletcher G.H. Malignant tumors of the major salivary glands.Radiology. 1971; 100: 381-384PubMed Google Scholar, 3Kadish S.P. Goodman M.L. Wang C.C. Treatment of minor salivary gland malignancies of upper food and air passage epithelium—A review of 87 cases.Cancer. 1972; 29: 1021-1026Crossref PubMed Scopus (12) Google Scholar, 4Ellis E.R. Million R.R. Mendenhall W.M. et al.The use of radiation therapy in the management of minor salivary gland tumors.Int J Radiat Oncol Biol Phys. 1988; 15: 613-617Abstract Full Text PDF PubMed Scopus (48) Google Scholar).The purpose of this study is to review a long-term, single-institution experience with the management of salivary gland carcinomas treated by definitive radiation therapy in an attempt to identify clinical and disease characteristics correlating with outcome.Methods and materialsPatient populationThis study was formally approved by the Institutional Review Board at the University of California, San Francisco (UCSF) School of Medicine before the collection and retrospective review of patient information. Between January 1960 and December 2004, 57 consecutive patients with a histologic diagnosis of salivary gland carcinoma localized to the head and neck were treated at UCSF with radiation therapy alone for gross disease. The following patients were excluded from this analysis: 6 patients treated for recurrent disease; 3 patients with evidence of distant metastasis at the time of radiation treatment; and 3 patients treated with palliative intent. Table 1 outlines the clinical and disease characteristics of the 45 remaining patients who received radiation therapy alone for previously untreated salivary gland carcinomas with definitive intent, comprising the primary population of this retrospective review. Indications for primary radiation treatment were as follows: 17 surgically unresectable (38%), 13 with gross residual disease after subtotal resection or open biopsy (29%), 12 medically inoperable (27%), and 3 refusal of surgery (7%). None of the patients had a history of receiving prior radiation therapy. Histologic subtype was as follows: 14 mucoepidermoid carcinoma (31%), 10 adenocarcinoma (22%), 8 adenoid cystic carcinoma (18%), 4 undifferentiated carcinoma (9%), 4 acinic cell carcinoma (9%), 2 malignant mixed carcinoma (4%), 2 squamous cell carcinoma (4%), and 1 salivary duct carcinoma (2%). Median age was 65 years (range, 37 to 93 years). Twenty-nine patients (64%) were male. Racial distribution was as follows: 29 Caucasian (64%), 6 Asian (13%), 5 Hispanic (11%), and 5 black (11%).Table 1Patient population (n = 45)CharacteristicNo. of patients (%)Primary site Parotid gland13 (29) Submandibular gland10 (22) Oropharynx7 (16) Oral cavity6 (13) Paranasal sinus6 (13) Nasopharynx/Nasal cavity3 (7)Histology High-grade mucoepidermoid4 (9) Low-grade mucoepidermoid6 (13) Mucoepidermoid, NOS2 (4) High-grade adenocarcinoma5 (11) Low-grade adenocarcinoma2 (4) Adenocarcinoma, NOS3 (7) Adenoid cystic8 (18) Undifferentiated4 (9) Acinic cell4 (9) Malignant mixed2 (4) Squamous cell2 (4) Salivary duct1 (2)T-stage 111 (24) 28 (18) 314 (31) 412 (27)Decade of treatment 1960s4 (9) 1970s10 (22) 1980s12 (27) 1990s11 (24) 2000s8 (18)Abbreviation: NOS = not otherwise specified. Open table in a new tab Staging evaluation consisted of history and physical examination, complete blood count, liver function tests, chest X-ray, and imaging of the primary site and regional lymph nodes. Twelve patients (27%) underwent magnetic resonance imaging of the head and neck as a component of the initial workup. Axial imaging with computed tomography has generally been a routine part of patient evaluation since it became available at UCSF in 1974. Tumors of the major salivary glands were retrospectively staged in accordance with the 2002 American Joint Committee on Cancer staging system. Those involving the minor salivary glands were staged using the criteria for squamous cell carcinoma in similar sites. The most common site of disease involvement was the parotid gland (13 patients), followed by the submandibular gland (10 patients), oropharynx (7 patients), oral cavity (6 patients), paranasal sinuses (6 patients), and nasopharynx/nasal cavity (3 patients). Distribution of T-stage was as follows: 24% T1, 18% T2, 31% T3, and 27% T4. The median tumor size, as determined by physical examination or radiographic imaging (or both), measured 3.4 cm (range, 1.2–9.2 cm) with 6 patients having tumors in excess of 7 cm. None of the patients had clinical or pathologic evidence of regional lymph node disease at the time of presentation.TreatmentRadiation technique varied depending largely on the site of disease, the time period of treatment, and the discretion of the radiation oncologist. All patients were treated with megavoltage equipment using photons or mixed photons and electrons. No patient was treated with neutrons. The treatment volume was designed to cover the primary site with 2–3-cm margins. The base of skull was routinely treated for all tumors with adenoid cystic histology. None of the patients received interstitial or intraoperative radiation therapy. Patients were treated with conventional fractionation, most commonly 2 Gy per fraction. Median dose was 66 Gy (range, 57–74 Gy). Treatment was by continuous-course external beam radiation with once-a-day treatment. The median elapsed time of treatment was 49 days (range, 43–62 days). All patients completed the planned course of treatment. Radiation therapy techniques included mixed photon-electron appositional fields (12 patients), wedged-pair fields (9 patients), three-field isocentric treatments (9 patients), and parallel-opposed lateral fields prescribed to midplane (8 patients). Wedges or tissue compensators were used to maintain dose homogeneity within 10% of the prescribed dose. Beginning in 1997, intensity-modulated radiation therapy was used and 7 patients were treated with this technique. Two patients (4%) received adjuvant chemotherapy, 1 concurrently with radiation therapy and 1 after completion of radiation therapy.Treatment of the neck was dependent on multiple factors. None of the patients had previously undergone a neck dissection. Elective neck radiation was administered at the discretion of the treating radiation oncologist with consideration given to the extensiveness and lymphatic drainage of the primary tumor site as well as the histologic subtype and tumor grade. Overall, 12 of the 45 patients (27%) received elective neck radiation to a median dose of 50 Gy (range, 45–54 Gy).Follow-up consisted of routine physical examination and imaging studies of the primary site. Patients were typically seen at 3-month intervals for 1 year and then annually thereafter. Patient follow-up was reported to the date last seen in clinic. Survival status was obtained from information provided by the UCSF Tumor Registry and from publicly accessible databases using patient social security numbers. In some cases, referring physicians were contacted to obtain information regarding patient health status.Endpoints and statistical analysisThe endpoints analyzed were local control, overall survival, and distant metastasis. All events were measured from the date of histologic diagnosis of the initial biopsy specimen. Local control was judged to have been attained if there was complete disappearance of the salivary gland carcinoma after radiation therapy and no evidence of tumor growth at the primary site based on clinical and radiographic findings at follow-up. Regional failure was recorded separately if there was evidence of an enlarging cervical or supraclavicular mass distinct from the primary site. Patients who did not achieve an initial complete response were considered as failures on Day 1. Median follow-up was 101 months for all patients (range, 3 to 285 months) and 123 months among surviving patients (range, 12 to 285 months). Five-year and 10-year estimates of the probability of overall survival, local control, and distant metastasis–free survival were calculated using the Kaplan-Meier method, with comparisons among groups performed with two-sided log–rank tests (5Kaplan E.L. Meier P. Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1958; 53: 547-581Crossref Scopus (47708) Google Scholar). A Cox proportional hazards model was used to identify independent predictors of local recurrence and distant metastasis (6Cox D.R. Oakes N. Analysis of survival data. Chapman and Hall, New York1988Google Scholar). Selection of variables to consider as predictors was based upon univariate analysis. A stepwise forward method was carried out and the likelihood ratio test was used to identify significant independent predictors of outcome. Hazard ratio parameters were determined using the Wald test. All tests were two-tailed, with a probability value of less than 0.05 considered statistically significant.ResultsLocal controlNineteen patients experienced a local recurrence, 13 of which were isolated first events. The median time to local recurrence was 2.0 years (range, 0–11.2 years) with 6 recurrences (32%) occurring more than 5 years from the time of initial diagnosis. For the entire patient population, the 5- and 10-year estimates of local control were 70% and 57%, respectively.Table 2 summarizes local control rates according to clinical and disease characteristics for the entire patient population. On univariate analysis, parameters predictive of decreased local control were stage T3–4 disease, minor salivary gland site, and the use of radiation doses less than 66 Gy. The 10-year rates of local control for patients with T1, T2, T3, and T4 tumors were 83%, 80%, 48%, and 30%, respectively (p = 0.11). However, when this analysis was repeated comparing patients with T1–2 tumors vs. those with T3–4 tumors, a significant difference in local control was observed (p = 0.03). As illustrated in Fig. 1, the 10-year rate of local control was 81% for patients with T1–2 tumors vs. 39% for patients with T3–4 tumors. With respect to primary tumor site, patients with tumors originating from the minor salivary glands had a 10-year local control of 44% compared with 65% for those with major salivary gland cancers (p = 0.04). When radiation dose was analyzed as a categorical variable using the median dose of 66 Gy as a cutpoint, a statistical difference in local control was observed favoring the higher dose (<66 vs. ≥66 Gy, p = 0.01). A statistically significant advantage in local control was also observed when patients treated with doses less than or equal to 66 Gy were compared with those treated with doses greater than 66 Gy (≤66 vs. >66 Gy, p = 0.01). Figure 2 demonstrates this dose–response relationship among all patients treated by radiation alone for salivary gland carcinomas. The 10-year rate of local control was 81% for patients treated with doses greater than 66 Gy compared with 40% for those who received doses lower than or equal to 66 Gy. The age at diagnosis (age ≥65 years vs. age <65 years), gender, and decade of treatment (before 1980 vs. after 1980) did not indicate a difference in local control (p > 0.05, for all).Table 2Local control by clinical and disease characteristicsFactor# Failures5-yr LC (%)10-yr LC (%)pT-stage0.11 T12 of 118383 T22 of 88080 T37 of 147148 T48 of 124230T-stage0.03 T1–24 of 198181 T2–315 of 265839Primary site0.04 Major gland8 of 237265 Minor gland11 of 226644Age, years0.29 <658 of 217358 ≥6511 of 246557Gender0.33 Male13 of 296754 Female6 of 167361Decade of treatment0.63 <19805 of 146955 >198014 of 317057RT dose0.01 >663 of 209281 ≤6616 of 255340Abbreviations: RT = radiation therapy; LC = local control. Open table in a new tab Fig. 2Local control for patients treated by radiation therapy alone for salivary gland carcinomas according to radiation dose received (≤66 vs. >66 Gy).View Large Image Figure ViewerDownload (PPT)A multivariate analysis of the entire patient sample was performed using a Cox proportional hazard model considering advanced T-stage (T3–4), minor salivary gland cancer site, and treatment with radiation doses less than 66 Gy as possible predictors of local recurrence. T3–4 disease and treatment with radiation doses less than 66 Gy were identified as significant independent predictors of local recurrence (likelihood ratio test: p = 0.004 and 0.001, respectively). Hazard ratios for local recurrence among those treated for T3–4 disease and with doses less than 66 Gy were 3.37 (95% confidence interval, 1.42–8.98) and 5.49 (95% confidence interval, 1.90–15.39), respectively.SurvivalTwenty-nine of the 45 patients treated have died at the time of this analysis. Figure 3 illustrates overall survival for all patients who completed definitive treatment with radiation therapy alone for salivary gland cancers. Overall survival at 5 and 10 years was 70% and 46%, respectively. Univariate analysis of the clinical and pathologic variables analyzed did not identify any differences in overall survival. Increased T-stage did not appear to be associated with decreased survival. The 5-year and 10-year estimates of overall survival were 65% and 43% for patients with T1 tumors, 76% and 51% for patients with T2 tumors, 71% and 45% for patients with T3 tumors, and 68% and 37% for those with T4 tumors, respectively (p = 0.44). The primary tumor site (major vs. minor salivary gland), age at diagnosis (age ≥65 years vs. age <65 years), gender, decade of treatment (before 1980 vs. after 1980), and radiation dose (<66 vs. ≥66 Gy) did not indicate a difference in overall survival (p > 0.05, for all).Fig. 3Overall survival for patients treated by radiation therapy alone for salivary gland carcinomas.View Large Image Figure ViewerDownload (PPT)Distant metastasisDistant metastases developed in 13 patients. Two patients had a simultaneous local recurrence, and 5 others had a previous local recurrence. Median time to the development of distant metastasis was 6.8 years (range, 0.8–12.5 years), with 7 cases (54%) occurring more than 5 years from the time of original diagnosis. As illustrated in Fig. 4, the actuarial distant metastases–free rates for the entire patient population were 85% and 67% at 5 and 10 years, respectively. Univariate analysis of the clinical and pathologic variables analyzed did not reveal any differences in overall survival with the exception of T-stage. The 5-year and 10-year distant metastasis–free rates were 93% and 83% for patients with T1–2 tumors compared with 74% and 60% for those with T3–4 tumors, respectively (p = 0.01).Fig. 4Distant metastases–free survival for patients treated by radiation therapy alone for salivary gland carcinomas.View Large Image Figure ViewerDownload (PPT)Sites of failureFive of the 19 local failures represented cases where the primary tumor was never initially controlled with radiation therapy based on imaging and clinical examination. Two patients experienced disease recurrence in the regional lymph nodes at 1.0 years and 3.3 years, respectively, after initial diagnosis. One of these was an isolated recurrence, and the other occurred simultaneously with the development of distant metastasis. Both patients underwent biopsies of suspicious appearing cervical neck nodes that revealed recurrent tumor consistent with the original histology (high-grade mucoepidermoid carcinoma and high-grade adenocarcinoma, respectively). Neither of these patients had previously received elective neck irradiation for what were staged as primary T3 cancers involving the parotid gland and hard palate, respectively. Initial sites of distant failure for the patient population were: 10 lung (77%), 2 bone (13%), and 1 liver (7%). There were no recurrences in the base of skull.DiscussionIn our previous analysis of patients with salivary gland cancers treated at UCSF between 1960 and 1978, 5 of 7 patients (71%) achieved initial control of the primary tumor after treatment with radiation therapy alone (7Fu K.K. Leibel S.A. Levine M.L. et al.Carcinoma of the major and minor salivary glands.Cancer. 1977; 40: 2882-2890Crossref PubMed Scopus (225) Google Scholar). This update of all patients treated to the present continues to refute the notion that salivary gland carcinomas represent a radioresistant group of tumors. On the contrary, our results, with long-term follow-up, demonstrate that a significant proportion of patients who are not candidates for surgical resection can be rendered disease-free with definitive radiation therapy alone. In addition, T3–4 disease and the use of radiation doses less than 60 Gy appear to be independent predictors of inferior local control after this approach.Our findings are consistent with the results of other single-institution reports with more limited follow-up. Wang and Goodman demonstrated 5-year overall survival and local control rates of 65% and 100%, respectively, among 9 patients treated with radiation alone using a hyperfractionated regimen for salivary gland carcinoma of the parotid gland at Massachusetts General Hospital (8Wang C.C. Goodman M. Photon irradiation of unresectable carcinomas of salivary glands.Int J Radiat Oncol Biol Phys. 1991; 21: 569-576Abstract Full Text PDF PubMed Scopus (52) Google Scholar). Hosokawa et al. reported 5-year overall survival and local control rates of 65% and 73%, respectively, among 33 patients treated at the Hokkaido University for primary adenoid cystic carcinoma of the salivary glands (9Hosokawa Y. Ohmori K. Kaneko M. et al.Analysis of adenoid cystic carcinoma treated by radiotherapy.Oral Surg Oral Med Oral Pathol. 1992; 74: 251-255Abstract Full Text PDF PubMed Scopus (25) Google Scholar). Douglas et al. reported 6-year cause-specific survival and local-regional control rates of 67% and 59%, respectively, among 263 patients with salivary gland carcinomas treated with fast neutron radiation therapy for gross disease at the University of Washington (10Douglas J.G. Koh W.J. Auston-Seymour M. et al.Treatment of salivary gland neoplasms with fast neutron radiotherapy.Arch Otolaryngol Head Neck Surg. 2003; 129: 944-948Crossref PubMed Scopus (101) Google Scholar). Most recently, Mendenhall et al. reported 10-year overall survival and local control rates of 65% and 75%, respectively, for patients treated with radiation alone for T1–3 salivary gland carcinoma at the University of Florida (11Mendenhall W.M. Morris C.G. Amdur R.J. et al.Radiotherapy alone or combined with surgery for salivary gland carcinoma.Cancer. 2005; 103: 2544-2550Crossref PubMed Scopus (150) Google Scholar). Similar to the present series, results for patients treated with T4 disease were less favorable with 10-year overall survival and local control rates of 21% and 21%, respectively.Differences in selection criteria and therapeutic approach most likely account for the discrepancies between observed outcomes across institutions. For instance, studies that demonstrated inferior outcomes frequently included patients treated with radiation alone for recurrent tumors or patients with metastatic disease. Similarly, imbalances in the proportion of patients with tumors originating from minor vs. major salivary gland sites could also have influenced observed outcomes, because it has been suggested that the latter group has a better prognosis (10Douglas J.G. Koh W.J. Auston-Seymour M. et al.Treatment of salivary gland neoplasms with fast neutron radiotherapy.Arch Otolaryngol Head Neck Surg. 2003; 129: 944-948Crossref PubMed Scopus (101) Google Scholar). Furthermore, salivary gland carcinomas represent a remarkably heterogeneous group of histologic subtypes, each with variable prognosis. Although the small number of patients in the present series precluded any formal subset analysis by histology, it is likely that this factor could contribute to reported differences in survival and local control for patients treated with radiation alone. Lastly, it is unknown how treatment strategy may have influenced outcome. Indeed, some investigators have suggested that techniques such as altered fractionation, fast neutron therapy, hyperthermia, and brachytherapy have the potential to improve results (12Barnett T.A. Kapp D.S. Goffinet D.R. Adenoid cystic carcinoma of the salivary glands.Cancer. 1990; 65: 2648-2665Crossref PubMed Scopus (17) Google Scholar, 13Armstrong J.G. Harrison L.B. Spiro R.H. et al.Brachytherapy of malignant tumors of salivary gland origin.Endocurither Hypertherm Oncol. 1996; 6: 19-22Google Scholar, 14Saroja K. Mansell J. Hendrikson F. et al.An update on malignant salivary gland tumors treated with neutrons at Fermilab.Int J Radiat Oncol Biol Phys. 1987; 13: 1319-1325Abstract Full Text PDF PubMed Scopus (48) Google Scholar, 15Catterall M. Errington R.D. The implications of improved treatment of malignant salivary gland tumors by fast neuron radiotherapy.Int J Radiat Oncol Biol Phys. 1987; 13: 1313-1318Abstract Full Text PDF PubMed Scopus (60) Google Scholar).The only randomized trial investigating the efficacy of primary radiation therapy for salivary gland carcinomas reported to date was conducted jointly by the Radiation Therapy Oncology Group (RTOG) and Medical Research Council (MRC) and compared neutron therapy to conventional radiation therapy with photons (16Laramore G.E. Krall J.M. Griffin T.W. et al.Radiation Therapy Oncology GroupNeutron versus photon irradiation for unresectable salivary gland tumors: Final report of an RTOG-MRC randomized clinical trial.Int J Radiat Oncol Biol Phys. 1993; 27: 235-240Abstract Full Text PDF PubMed Scopus (213) Google Scholar). Unfortunately, the small number of evaluable patients (13 and 12 patients on the neutron and photon arms, respectively) made drawing conclusions difficult because of imbalances in the distribution of important prognostic variables between the groups. For instance, 33% of the patients on the photon therapy arm had salivary gland tumors of squamous cell histology, a relatively rare and aggressive cancer, as compared with 8% on the neutron therapy arm. Similarly, none of the patients treated with photons had acinic cell histology as compared with 23% of the patients treated with neutrons. Moreover, it is important to realize that the RTOG/MRC trial was designed for unresectable salivary gland cancers. Although the specific T-stages were never reported, it is likely that the majority of the patients had T4 lesions based on contemporary staging criteria. Indeed, the median tumor size for patients treated with photons was 7.0 cm, with 1 patient having a tumor measuring 16.0 cm. In contrast, the median tumor size in the present series was 3.4 cm. It is also notable that 25% of the patients treated with photons on the RTOG/MRC trial had recurrent cancers and 33% had clinical lymph node involvement compared with 0% and 0%, respectively, in the present study. Lastly, a significant proportion of patients treated on the photon therapy arm was treated to a total dose of 55 Gy, which may have been suboptimal. Given the biases discussed above, it is hardly surprising that the local-regional control for patients treated with photons was only 17%.Our findings suggest that a dose–response relationship might exist for salivary gland carcinomas treated with radiation therapy alone. This is consistent with reports from other series. In the University of Florida series, a dose greater than 70 Gy resulted in better outcome than less than 70 Gy, particularly for adenoid cystic carcinoma (17Parsons J.T. Mendenhall W.M. Stringer S.P. et al.Management of minor salivary gland carcinomas.Int J Radiat Oncol Biol Phys. 1996; 35: 443-454Abstract Full Text PDF PubMed Scopus (90) Google Scholar). Terhaard et al. also observed a dramatic dose–response relationship among 40 patients treated with primary radiation therapy at centers of the Dutch Head and Neck Oncology Cooperative Group (18Terhaard C.H.J. Lubsen H. Rasch C.R.N. et al.The role of radiotherapy in the treatment of malignant salivary gland tumors.Int J Radiat Oncol Biol Phys. 2005; 61: 103-111Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar). Similar to our results, the 5-year local control was 50% for patients treated to a dose of 66 Gy or greater, but 0% for patients treated to a dose of less than 66 Gy.Another issue is the optimal treatment volume, which focuses on the issue of elective nodal irradiation. Notably, there was only one isolated nodal failure in the present series despite the fact that less than one-third of the population actually received elective neck irradiation. This can be partially explained by the fact that the two most common histologic subtypes observed were adenoid cystic carcinoma and low-grade mucoepidermoid carcinoma, two cancers with a fairly low incidence of regional involvement. It is also likely that the judicious use of elective neck irradiation for patients believed to be at high risk for subclinical involvement contributed to the excellent rate of regional control. Several studies have demonstrated that the incidence of occult lymph node involvement for salivary gland cancers is related to tumor histology and primary size, and our current policy regarding elective nodal irradiation takes into account the draining lymphatics of the primary site, histologic subtype, and T-stage (19Armstrong J.G. Harrison L.G. Spiro R.H. et al.The indications for elective neck treatment of the neck in cancer of the major salivary glands.Cancer. 1992; 69: 615-619Crossref PubMed Scopus (268) Google Scholar, 20Regis de Brito Santos I. Kowalkso L.P. Cavalcante de Araujo V. et al.Multivariate analysis of risk factors for neck metastases in surgically treated parotid carcinomas.Arch Otolarnygol Head Neck Surg. 2001; 127: 56-60Crossref PubMed Scopus (117) Google Scholar, 21Rodriguez-Cuevas S. Labastida S. Baena L. et al.Risk of nodal metastases from malignant salivary gland tumors related to tumor size and grade of malignancy.Eur Arch Otorhinolaryngol. 1995; 252: 139-142PubMed Google Scholar).Despite our relatively favorable results with the use of radiation therapy alone for the definitive treatment of salivary gland carcinomas, we maintain that surgery with or without postoperative radiation therapy remains the standard of care, at least for T3–4 lesions. For patients with smaller tumors, it appears that radiation therapy alone achieves similar rates of disease control for those treated by resection. Although a randomized comparison will likely never be performed owing to preexisting treatment biases and the relatively infrequent incidence of salivary gland carcinomas, our data demonstrate that primary radiation therapy is a feasible option for appropriately selected patients desiring a nonsurgical approach. Although retrospective series reporting on outcome after surgery for malignancies of the salivary glands are generally limited by institutional prejudices regarding inclusion criteria and treatment decisions, large-scale studies have demonstrated long-term survival rates between 80–90% and local control rates on the order of 70–80% (22Kirkbride P. Liu F.F. O’Sullivan B. et al.Outcome of curative management of malignant tumors of the parotid gland.J Otolaryngol. 2001; 30: 271-279Crossref PubMed Scopus (34) Google Scholar, 23Garden A.S. El-Naggar A.K. Morrison W.H. et al.Postoperative radiation therapy for malignant tumors of the parotid gland.Int J Radiat Oncol Biol Phys. 1997; 37: 79-85Abstract Full Text PDF PubMed Scopus (160) Google Scholar, 24North C.A. Lee D.J. Piantadosi S. et al.Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy.Int J Radiat Oncol Biol Phys. 1990; 18: 1319-1326Abstract Full Text PDF PubMed Scopus (167) Google Scholar). Nonetheless, it is important to recognize that the observed differences in outcomes between the present series and those using primary surgery for the definitive management of salivary gland carcinomas are likely due in part to selection bias, because in many instances, patients referred for radiation therapy had worse performance status, were less rigorously staged, and were of more advanced age with comorbid illnesses. The primary limitation of this study was that because of the retrospective nature of this report, we were unable to determine with certainty the actual cause of death for each patient who expired. We were thus unable to report cause-specific survival for this series, which would be higher than overall survival simply because a sizable proportion of the deaths were in all likelihood not cancer related. It is notable that for patients treated with definitive radiation at other disease sites, clinical parameters such as pretreatment performance status and weight loss have been shown to have prognostic value (25Jeremic B. Classen J. Bamberg M. Radiotherapy alone in technically operable, medically inoperable, early-stage (I/II) non–small cell lung cancer.Int J Radiat Oncol Biol Phys. 2002; 54: 119-130Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 26Werner-Wasik M. Scott C. Cox J.D. et al.Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non–small-cell lung cancer (LA-NSCLC): Identification of five groups with different survival.Int J Radiat Oncol Biol Phys. 2000; 48: 1475-1482Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 27Coia L.R. Minsky B.D. Berkey B.A. et al.Outcome of patients receiving radiation for cancer of the esophagus: Results of the 1992–1994 Patterns of Care Study.J Clin Oncol. 2000; 18: 455-462Crossref PubMed Google Scholar). Although the significance of these variables could not be analyzed retrospectively in this present series, it is not unreasonable to assume that they may have been of importance in predicting outcome for patients treated with definitive radiation for salivary gland carcinomas.Although the present report does not examine complications secondary to treatment, results from other groups have shown that radiation therapy for salivary gland malignancies is in general well tolerated (28Huber P.E. Debus J. Latz D. et al.Radiotherapy for advanced adenoid cystic carcinoma: Neutrons, photons, or mixed beam?.Radiother Oncol. 2001; 59: 161-167Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 29Le Q.T. Birdwell S. Terris D.J. et al.Postoperative irradiation of minor salivary gland malignancies of the head and neck.Radiother Oncol. 1999; 52: 165-171Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 30Bragg C.M. Conway J. Robinson M.H. et al.The role of intensity-modulated radiotherapy in the treatment of parotid tumors.Int J Radiat Oncol Biol Phys. 2002; 52: 729-738Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). With the widespread adoption of more conformal techniques such as intensity-modulated radiation therapy for the treatment of head-and-neck cancers, it is likely that the potential to reduce toxicity in the setting of dose-escalation will lead to increasingly recognizable clinical benefits. While subject to the inherent limitations of any retrospective study, our results demonstrate that radiation therapy alone can achieve long-term survival in a significant percentage of patients treated and should continue to be offered to selected patients seeking an alternative to surgery for salivary gland carcinomas. Continued follow-up is paramount, however, as late recurrences are not uncommon for patients with salivary gland cancer. Studies should continue to focus on identifying the optimal dose and fractionation regimen for patients treated by radiation alone for salivary gland carcinomas in the future. IntroductionMalignant tumors of the salivary glands account for approximately 3% of all head-and-neck cancers (1Foote R.L. Olsen K.D. Bonner J.A. et al.Salivary gland cancer.in: Gunderson L.L. Tepper J.E. Clinical radiation oncology. Churchill Livingstone, Philadelphia2000: 518-534Google Scholar). While surgical excision forms the mainstay of treatment, a small proportion of newly diagnosed patients are either not candidates for definitive resection or undergo limited procedures leaving behind gross residual disease. Typically, these patients are deemed inoperable because of technical issues related to the extensiveness or location of the primary tumor. However, another subset of inoperable patients present with medical comorbidities that places them at unacceptably high risk for perioperative complications. Lastly, some patients refuse surgical therapy out of personal preference. Regardless of the underlying reasons, these inoperable patients have all traditionally been offered definitive radiation therapy as an alternative to surgery for the primary treatment of their salivary gland tumors. Although carcinomas originating from the salivary glands were once thought to be radioresistant with radiation alone reserved for palliation, it is becoming increasingly evident that cure may be possible in appropriately selected patients (2King J.J. Fletcher G.H. Malignant tumors of the major salivary glands.Radiology. 1971; 100: 381-384PubMed Google Scholar, 3Kadish S.P. Goodman M.L. Wang C.C. Treatment of minor salivary gland malignancies of upper food and air passage epithelium—A review of 87 cases.Cancer. 1972; 29: 1021-1026Crossref PubMed Scopus (12) Google Scholar, 4Ellis E.R. Million R.R. Mendenhall W.M. et al.The use of radiation therapy in the management of minor salivary gland tumors.Int J Radiat Oncol Biol Phys. 1988; 15: 613-617Abstract Full Text PDF PubMed Scopus (48) Google Scholar).The purpose of this study is to review a long-term, single-institution experience with the management of salivary gland carcinomas treated by definitive radiation therapy in an attempt to identify clinical and disease characteristics correlating with outcome.

To evaluate the impact of postoperative radiation therapy on the clinical course of patients with carcinoma ex pleomorphic adenoma of the parotid gland.Between 1960 and 2004, 63 patients were treated with definitive surgery for carcinoma ex pleomorphic adenoma of the parotid gland. Forty patients (63%) received postoperative radiation therapy to a median dose of 60 Gy (range, 45-71 Gy). Adenocarcinoma (29 patients), salivary duct carcinoma (16 patients), and adenoid cystic carcinoma (9 patients) were the most common malignant subtypes. Pathologic T -stage was: 16% T1, 33% T2, 32% T3, and 19% T4. Twenty-one patients (33%) had microscopically positive margins and 39 (62%) had perineural invasion. Median follow-up was 50 months (range, 2-96 months).The use of postoperative therapy significantly improved 5-year local control from 49% to 75% (p = 0.005) and was associated with an improvement in survival among patients without evidence of cervical lymph node metastasis (p = 0.01). A Cox proportional hazard model identified pathologic involvement of cervical lymph nodes as an independent predictor of overall survival. Overall survival was 16% for patients with pathologic N-positive disease compared with 67% for those whose lymph node status was negative or unknown (p = 0.001).Surgery followed by postoperative radiation should be considered the standard of care for patients with carcinoma ex pleomorphic adenoma.

Abstract Facial nerve monitoring is an adjunctive method available to a surgeon during parotid surgery to assist with the functional preservation of the facial nerve. This review describes the goals, applications, technique, and benefits of electrophysiologic facial nerve monitoring during parotid surgery. A review and analysis of the relevant medical literature related to electrophysiologic facial nerve monitoring during parotid surgery are included. © 2009 Wiley Periodicals, Inc. Head Neck, 2010

This review summarises the contemporary, multidisciplinary approach to managing parapharyngeal space neoplasms.Parapharyngeal space neoplasms are uncommon head and neck tumours and are most often benign. Most tumours are of either salivary gland or neurogenic origin. Patients tend to be asymptomatic even when tumours reach large sizes. Patients may present with a mass in the pharynx or neck, although frequently the tumour is found incidentally on an imaging study. Due to the limitations of physical examination in this anatomical area, imaging studies are essential to the evaluation of parapharyngeal space neoplasms. Cytopathology may provide additional diagnostic information. Open biopsy is rarely necessary and can be hazardous. Treatment is primarily surgical, and various surgical approaches can be tailored for a given neoplasm. Recently, a trend toward observation of select patients with asymptomatic neurogenic tumours has been advocated.The evaluation and management of parapharyngeal space tumours is best done by a multidisciplinary team. Treatment should be individualised, and the risks and benefits of surgical intervention need to be carefully weighed. Complications are best avoided by careful surgical planning.

Objective To examine 30‐day readmission rates and associations with risk factors, survival, length of hospitalization, and costs in elderly patients with laryngeal and oropharyngeal squamous cell cancer (SCC). Study Design Retrospective cross‐sectional analysis of Surveillance, Epidemiology, and End Results‐Medicare data. Methods We evaluated 1,518 patients diagnosed with laryngeal or oropharyngeal SCC from 2004 to 2007 who underwent primary surgery using cross‐tabulations, multivariate regression modeling, and survival analysis. Results Thirty‐day readmission occurred in 14.1% of hospitalizations. Readmission was more likely in patients with postoperative complications during initial hospitalization (24.8% vs. 4.5%, P &lt; 0.001), and was associated with an increased 30‐day mortality incidence rate (5.1% vs. 0.9%; P &lt; 0.001). On multivariate analysis, 30‐day readmission was significantly associated with advanced stage (odds ratio [OR] = 1.81 [1.13–2.90]), comorbidity (OR = 2.69 [1.65–4.39]), divorced/separated marital status (OR = 2.00 [1.19–3.38]), preoperative tracheostomy (OR = 3.39 [1.55–7.44]), major surgical procedures (OR = 2.58 [1.68–3.97]), greater length of initial hospitalization (OR = 1.72 [1.09–2.71]), pneumonia (OR = 2.86 [1.28–6.40]), postoperative dysphagia (OR = 5.97 [2.48–15.83]), and cardiovascular events (OR = 5.84 [1.89–17.96]). Thirty‐day readmission was significantly associated with 30‐day mortality (OR = 5.89 [2.21–15.70) and higher 1‐year mortality (68.0% vs. 89.2%, P &lt; 0.001). The mean incremental costs of surgical care were significantly greater for patients with unplanned readmission ($15,123 [$10,514–$19,732]), after controlling for all other variables. Conclusion Unplanned readmissions are associated with increased short‐ and long‐term mortality and costs. Elderly patients with advanced disease, advanced comorbidity, lack of spousal support, pretreatment organ dysfunction, more extensive surgery, postoperative pneumonia, postoperative dysphagia, and prolonged hospitalization are at increased risk of 30‐day readmission. These findings suggest a need for targeted interventions before, during, and after hospitalization to reduce morbidity, mortality, and excess costs in this high‐risk population. Level of Evidence 2c. Laryngoscope , 127:631–641, 2017

BACKGROUND The incidence of oropharyngeal cancer (OPC) and a subset of oral cavity cancer (OCC) is increasing in the United States. To the authors' knowledge, the presumed growing prevalence of survivors of OPC and OCC has not been investigated to date. METHODS Retrospective analysis of Surveillance, Epidemiology, and End Results data (1975‐2012) estimated changes in incidence, 5‐year cause‐specific survival, and prevalence for OPC and OCC. Changes in incidence, cause‐specific survival and prevalence were estimated by linear regression and expressed as the percentage change ( B ). Differences in incidence trends over time were determined by joinpoint analysis. RESULTS The incidence of OPC increased by 62.6% from 1975 through 2012. Notable increases in OPC incidence were observed among men, white individuals, and those of younger ages. The 5‐year survival for OPC increased significantly for all sexes, races, and individuals aged &gt;30 years, with white individuals and males experiencing the largest increase in survival. By contrast, the incidence of OCC declined by 22.3% during the same time period. OCC incidence decreased across all groups but increased among individuals aged 30 to 39 years. Significant increases in survival were observed for OCC, except for those who were female, black, and aged &lt;40 years. The prevalence of survivors of OPC increased from 2000 to 2012 ( B , 115.1 per 100,000 individuals per year; P &lt;.0001), whereas the prevalence of survivors of OCC significantly decreased ( B , −15.8 per 100,000 individuals per year; P &lt;.0001). CONCLUSIONS The prevalence of survivors of OPC is increasing, whereas the prevalence of survivors of OCC is declining. These data portend significant implications for long‐term care planning for survivors of OPC and OCC. Cancer 2016;122:1380–1387 . © 2016 American Cancer Society .

To describe a 10-year diversity initiative to increase the number of women and underrepresented minorities in an academic department of otolaryngology-head and neck surgery.Retrospective review.A multifaceted approach was undertaken to recruit and retain women and underrepresented minority (URM) faculty: creation of a climate of diversity, aggressive recruitment, achievement of parity of salary at rank regardless of gender or minority status, provision of mentorship to women and URM faculty, and increasing the pipeline of qualified candidates. Primary outcomes measures included number of women and URM faculty, academic rank, and salary.From 2004 to 2014, the percentage of women clinical faculty increased from 5.8% to 23.7%; women basic science faculty increased from 11.1% to 37.5%. The number of women at associate professor rank increased from 0 to eight. During this period, underrepresented minority faculty increased in number from two to four; URM full professors increased in number from 0 to 1. In 2004, women earned 4% to 12% less than their male counterparts; there were no salary differences for URM. In 2014, salary was equal by rank and subspecialty training independent of gender or minority status.A comprehensive diversity and inclusion initiative has increased representation of women and URM faculty in an academic department of otolaryngology-head and neck surgery. However, there continue to be opportunities to further increase diversity.N/A.

The aim of this study was to evaluate the prevalence of comorbidities among patients with head and neck squamous cell carcinoma (HNSCC) at the time of their cancer diagnosis and during their survivorship trajectory. The second aim was to evaluate the differences in comorbidities developed according to treatment type received.Retrospective cross-sectional.SEER (Surveillance, Epidemiology, and End Results)-Medicare linked database.Individuals with a first-incident primary diagnosis of HNSCC from 2004 to 2011 per the SEER-Medicare database were included in analysis. The presence or absence of 30 comorbid conditions of interest was identified during distinct periods and analyzed according to treatment with surgery alone, primary (chemo)radiation, or surgery with (chemo)radiation.The study population consisted of 10,524 individuals diagnosed with HNSCC, with a mean age of 74.8 years. At diagnosis, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and diabetes were the most prevalent comorbidities, and they increased over time. The probability of developing treatment-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in the short and long term following treatment ( P < .05). By 5 years from cancer diagnosis, patients were most likely to have newly diagnosed hypertension, dysphagia, anemia, and weight loss. Primary surgery alone was associated with a lower risk of diagnosis with these treatment-related comorbidities, as compared with treatments involving radiation therapy and/or chemotherapy in the primary or adjuvant settings ( P < .05).There is a large burden of comorbidities among patients following HNSCC treatment, which warrant clinical attention during surveillance.

Human papillomavirus (HPV) is responsible for increasing incidence of oropharyngeal cancer. At present, there are no biomarkers in the surveillance algorithm for HPV-positive oropharyngeal cancer (HPV-OPC). HPV16 E6 antibody precedes oropharyngeal cancer diagnosis. If HPV16 E6 indeed precedes primary diagnosis, it is similarly expected to precede disease recurrence and may have a potential role as a biomarker for surveillance of HPV-OPC. To determine whether HPV antibody titers have a potential role as early markers of disease recurrence or prognosis, a retrospective pilot study was designed to determine whether HPV16 early antibody titers E6, E7, E1, and E2 decrease after treatment of HPV16-positive OPC. Trends in pretreatment, early (≤6 months after treatment), and late posttreatment (>6 months after treatment) HPV16 antibody titers were examined. There were 43, 34, and 52 subjects with serum samples available for pretreatment, early, and late posttreatment intervals. Mean pretreatment antibody levels were higher than posttreatment antibody levels. Average antibody levels decreased significantly over time for E6 (Ptrend = 0.001) and E7 (Ptrend < 0.001). Six disease recurrences were observed during the follow-up period (median, 4.4 years). In univariate analysis, a log-unit increase in pretreatment E6 titer was significantly associated with increased risk of disease recurrence (HR, 5.42; 95% CI, 1.1-25.7; P = 0.03). Therefore, levels of antibodies to HPV16 early oncoproteins decline after therapy. Higher E6 titers at diagnosis are associated with significant increases in the risk of recurrence. These data support the prospective evaluation of HPV16 antibodies as markers of surveillance and for risk stratification at diagnosis.

BACKGROUND The increasing incidence of oropharyngeal squamous cell cancer (OPSCC) is well established. However, up‐to‐date incidence estimates and trends for head and neck squamous cell cancers (HNSCCs) overall, including major anatomic sites, and nonoropharyngeal (non‐OP) HNSCCs by sex, race, and age in the United States are not well described. METHODS A retrospective analysis of incident HNSCCs during 1992 through 2014 using the Surveillance, Epidemiology, and End Results database was performed to evaluate the incidence of HNSCCs overall, OPSCC, and non‐OP HNSCC (those of the larynx, oral cavity, hypopharynx, nasopharynx, and nasal cavity). Incidence rates were calculated overall and by subgroups of interest, and incidence rate ratios were used to compare rates between groups. The incidence rates presented were per 100,000 population and were age adjusted to the 2000 US standard population (19 age groups; Census P25‐1130). The annual percent change (APC) was modeled with and without joinpoints. RESULTS The incidence of HNSCC overall declined (average APC [aAPC], ‐0.8; P &lt;.001) despite significant increases in the incidence of OPSCCs, most notably between 2000 and 2014 (APC, 2.1; P &lt;.001). Significant declines in incidence were observed for all non‐OP HNSCC sites for both women and men ( P &lt;.001 each). Among women, the risk of OPSCC also significantly decreased (aAPC, ‐0.8; P = .002), whereas the risk among men was stable during 1992 through 2001 (APC, 0.4; P = .42) and then significantly increased from 2001 to 2014 (APC, 2.7; P &lt;.001). Decreases in the risk of non‐OP HNSCC were especially large for black women (aAPC, ‐2.6; P &lt;.001) and men (aAPC, ‐3.0; P &lt;.001). Although the incidence of HNSCC previously was highest among black individuals, since 2009 its incidence has been higher among white compared with black individuals. CONCLUSIONS The incidence of HNSCC is declining, especially for non‐OP HNSCC and among black individuals. Cancer 2018;124:2125‐33 . © 2018 American Cancer Society .

Over the past 30 years, hypoglossal nerve stimulation has moved through a development pathway to become a viable treatment modality for patients with OSA. Initial pilot studies in animals and humans laid the conceptual foundation for this approach, leading to the development of fully implantable stimulating systems for therapeutic purposes. These devices were then shown to be both safe and efficacious in feasibility studies. One such closed-loop stimulating device was found to be effective in treating a limited spectrum of apneic patients and is currently approved by the US Food and Drug Administration for this purpose. Another open-loop stimulating system is currently being rigorously tested in a pivotal trial. Collectively, clinical trials of hypoglossal nerve stimulating systems have yielded important insights that can help optimize therapeutic responses to hypoglossal nerve stimulation. These insights include specific patient selection criteria and methods for delivering stimulation to specific portions of the hypoglossal nerve and/or genioglossus muscle. New approaches for activating efferent and afferent motor pathways are currently in early-stage laboratory development and hold some long-term promise as a novel therapy.

The association between pretreatment nutritional status and immunotherapy response in patients with advanced head and neck cancer is unclear. We retrospectively analyzed a cohort of 99 patients who underwent treatment with anti-PD-1 or anti-CTLA-4 antibodies (or both) for stage IV HNSCC between 2014 and 2020 at the Johns Hopkins Hospital. Patient demographics and clinical characteristics were retrieved from electronic medical records. Baseline prognostic nutritional index (PNI) scores and pretreatment body mass index (BMI) trends were calculated. Associations between PNI and BMI were correlated with overall survival (OS), progression-free survival (PFS), and immunotherapy response. In univariate analysis, there was a significant correlation between OS and PFS with baseline PNI (OS: HR: 0.464; 95% CI: 0.265-0.814; PFS: p = 0.007 and HR: 0.525; 95% CI: 0.341-0.808; p = 0.003). Poor OS was also associated with a greater decrease in pretreatment BMI trend (HR: 0.42; 95% CI: 0.229-0.77; p = 0.005). In multivariate analysis, baseline PNI but not BMI trend was significantly associated with OS and PFS (OS: log (HR) = -0.79, CI: -1.6, -0.03, p = 0.041; PFS: log (HR) = -0.78, CI: -1.4, -0.18, p = 0.011). In conclusion, poor pretreatment nutritional status is associated with negative post-immunotherapy outcomes.

The major goal of the study was to determine whether changes in tongue morphology under selective hypoglossal nerve therapy for obstructive sleep apnea were associated with alterations in airway patency during sleep when specific portions of the hypoglossal nerve were stimulated.This case series was conducted at the Johns Hopkins Sleep Disorders Center at Johns Hopkins Bayview Medical Center. Twelve patients with apnea implanted with a multichannel targeted hypoglossal nerve-stimulating system underwent midsagittal ultrasound tongue imaging during wakefulness. Changes in tongue shape were characterized by measuring the vertical height and polar dimensions between tongue surface and genioglossi origin in the mandible. Changes in patency were characterized by comparing airflow responses between stimulated and adjacent unstimulated breaths during non-rapid eye movement sleep.Two distinct morphologic responses were observed. Anterior tongue base and hyoid-bone movement (5.4 [0.4] to 4.1 [1.0] cm (median and [interquartile range]) with concomitant increases in tongue height (5.0 [0.9] to 5.6 [0.7] cm) were associated with decreases in airflow during stimulation. In contrast, comparable anterior hyoid movement (tongue protrusion from 5.8 [0.5] to 4.5 [0.9] cm) without significant increases in height (5.2 [1.6] to 4.6 [0.8] cm) were associated with marked increases in airflow during sleep.Tongue protrusion with preservation of tongue shape predicted increases in patency, whereas anterior movement with concomitant increases in height were associated with decreased pharyngeal patency. These findings suggest that pharyngeal patency can be best stabilized by stimulating lingual muscles that maintain tongue shape while protruding the tongue, thereby preventing it from prolapsing posteriorly during sleep.Fleury Curado T, Pham L, Otvos T, et al. Changes in tongue morphology predict responses in pharyngeal patency to selective hypoglossal nerve stimulation. J Clin Sleep Med. 2023;19(5):947-955.

To review the circumstances, complications, and outcomes of emergency surgical airway procedures and to compare the relative merits of cricothyroidotomy and tracheotomy for airway control in a hospital-wide patient population.Retrospective review.Patient data were obtained from the inpatient charts and electronic patient records of 35 patients who required an emergency surgical airway over a 6-year period at an urban medical center.Emergency cricothyroidotomy and tracheotomy were successfully performed in 34 of 35 patients (97%). Orotracheal intubation was successfully achieved in one patient with a failed cricothyroidotomy. The overall complication rates for emergency cricothyroidotomy and tracheotomy were similar (20% and 21%, respectively). Inpatients requiring an emergency surgical airway had a higher complication rate (32% vs. 0%) but better overall survival (91% vs. 46%) than patients treated in the emergency department. No long-term complications were observed from emergency cricothyroidotomies that were not converted to tracheotomies.The establishment of an emergency surgical airway by either tracheotomy or cricothyroidotomy is effective with low overall morbidity. The need to convert every emergency cricothyroidotomy to a tracheotomy should be reevaluated.

<h3>Objective:</h3> To evaluate the effect of electrical stimulation of hypoglossal nerve branches and ansa cervicalis nerve branches on upper airway patency. <h3>Design:</h3> Pressure-flow relationships obtained during supramaximal stimulation of hypoglossal nerve branches and ansa cervicalis nerve branches were analyzed in the isolated feline upper airway to determine the maximum inspiratory airflow as well as to determine pharyngeal collapsibility (upper airway critical pressure) and nasal resistance upstream from the site of pharyngeal collapse. Comparisons were performed between baseline and stimulation conditions with paired two-tailed<i>t</i>tests. <h3>Results:</h3> Stimulation of the proximal hypoglossal nerve trunk, distal medial hypoglossal nerve branch, nerve branches to the suprahyoid muscles, the infrahyoid muscles, and the suprahyoid and infrahyoid muscles simultaneously increased maximum inspiratory airflow significantly by decreasing airway collapsibility. A greater reduction in airway collapsibility was observed with stimulation of the tongue muscles compared with stimulation of the strap muscles. <h3>Conclusions:</h3> Stimulation of specific hypoglossal and ansa cervicalis nerve branches consistently increased maximum inspiratory airflow by decreasing airway collapsibility. The major decrease in airway collapsibility from hypoglossal nerve stimulation is dependent on the action of the genioglossus muscle. (Arch Otolaryngol Head Neck Surg. 1995;121:1361-1364)

Objective: To examine patient characteristics, pathologic features, and treatment outcomes of adenoid cystic carcinoma of the major salivary glands. Study Design: Retrospective review of patients in an academic medical center. Method: Review of medical records regarding demographics, extent of tumor, stage, histologic characteristics, and treatment outcomes of patients treated with surgery and postoperative radiation. Results: Of the 33 patients, 19 (58%) were male, and 14 (42%) were female. The average age of presentation was 49 (range 22–81) years. Of the 29 patients fully staged at the time of diagnosis, 7 (24%) presented at American Joint Committee on Cancer stage I, 9 (31%) at stage II, 4 (14%) at stage III, and 9 (31%) at stage IV. The cribriform histologic subtype was predominant (64%). The majority originated in the parotid gland (21, 64%), with the remaining originating in either the submandibular gland (10, 30%) or the sublingual gland (2, 6%). Local control was 94% at 5 years and 73% at 10 years. Metastatic control was 82% at 5 years and 63% at 10 years. Four patients failed locally and nine failed distally. Overall survival was 85% at 5 years and 69% at 10 years, with a median of 12.9 years. Conclusion: Surgical excision with postoperative radiation provides a long period of disease-free survival. Patients were more likely to fail with metastases than with local recurrence.

Intractable aspiration is a severe and often fatal complication in patients with impaired protective function of the larynx. This problem is usually a result of central nervous system disorders such as cerebrovascular accident, trauma, neoplasms, or degenerative disease. Surgical separation of the upper respiratory tract from the digestive tract can prevent recurrent contamination of the respiratory system in these patients. Two such procedures are the tracheoesophageal diversion procedure and a modification of this operation, the laryngotracheal separation procedure. The Virginia Mason Medical Center experience with these procedures, their indications, technique, and outcome are presented. In addition, cases of successful surgical reversal of the diversion procedures are discussed.

Impaired protective function of the larynx can lead to intractable aspiration, a severe and potentially fatal disorder. If medical therapy fails to prevent intractable aspiration, surgical separation of the upper respiratory tract from the digestive tract is necessary to prevent recurrent contamination of the respiratory system in these patients. Two such surgical procedures are the tracheoesophageal diversion procedure and the laryngotracheal separation procedure. Our approach to patients with intractable aspiration and the indications for the use of these surgical procedures for the prevention of aspiration are discussed.

Much of our understanding of human cancer has come from studies of the hereditary cancer predisposition syndromes. Fanconi anemia (FA) is an autosomal recessive disorder characterized by cellular hypersensitivity to DNA crosslinking agents, progressive bone marrow failure, and cancer predisposition to solid malignancies, especially head and neck squamous cell carcinoma (HNSCC). Since FA pathway-deficient cells are hypersensitive to DNA crosslinking chemotherapy agents, the presence of somatic FA gene inactivation in sporadic cancers may be of clinical interest. This study sought to determine the frequency of FA gene downregulation in sporadic HNSCC.The expression of the FA genes FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCJ, FANCL and FANCM in 11 HNSCC cell lines and 49 tongue carcinoma samples was studied with quantitative real-time polymerase chain reaction.Downregulation of at least one FA gene was observed in 3 of 11 HNSCC cell lines and 66% of tongue carcinoma samples. FANCB, FANCF, FANCJ and FANCM were most commonly affected by downregulation, whereas downregulation of FANCA, FANCE and FANCD2 was rare.Our data suggest that downregulation of FA genes is common in sporadic HNSCC. The clinical implications of this finding merit further study. .

Abstract Background Tumors involving the parapharyngeal space present a challenge of surgical access. Methods We reviewed all parapharyngeal space tumors resected at the University of California, San Francisco, between 2003 and 2006 and identified 14 patients who had a mandibular osteotomy to enhance surgical access to the parapharyngeal space. Results The surgical approach for the 14 patients who had a mandibulotomy was accomplished via either 1 or 2 mandibular osteotomies. A single paramedian osteotomy between the canine and the first premolar was used in 4 cases, whereas a combination of a horizontal osteotomy above the lingula and a paramedian osteotomy between the canine and first premolar was employed in 8 cases. A lingual dental splint and rigid fixation were used to achieve mandibular stabilization and fixation. Conclusion We found that the single and double mandibular osteotomies provided excellent surgical access allowing for total tumor removal with few sequelae. © 2008 Wiley Periodicals, Inc. Head Neck, 2009

Introduce the Chronic Obstructive Sialadenitis Symptoms (COSS) questionnaire to quantify chronic sialadenitis symptoms and assess the impact of sialendoscopic-assisted salivary duct surgery (SASDS).Retrospective outcome symptoms questionnaire study.The COSS questionnaire assesses the severity of sialadenitis symptoms from 0 to 100. Patients who underwent SASDS from April 2006 to December 2013 completed the COSS questionnaire and the ShortForm8 Health Survey (SF-8) based on current symptoms, and reported whether they had complete, partial, or no symptomatic response to SASDS.Sixty-six of the 156 (43%) contacted patients completed the questionnaires who had had symptoms in 26 submandibular ducts and 53 parotid ducts. The mean COSS score was higher for parotid ducts (12.0; interquartile range [IQR] 1.0-20.0) than for submandibular ducts (7.6; IQR 0.5-15.0) but not significantly so (P = 0.20). Thirty-eight (60%) patients reported complete resolution of symptoms, with a mean COSS score of 4.5 (IQR 0-7). Twenty-one (33%) patients reported partial resolution, with a mean COSS score of 18.5 (IQR 11.3-22.8). Five (8%) patients reported no improvement, with a mean COSS score of 25.1 (IQR 15.2-35). Thirty-six (46%) ducts with sialoliths had a significantly lower mean COSS score (5.8; IQR 0-9.5) compared to those without sialoliths (14.2; IQR 4.5-21.5, P = 0.0004). There was no significant difference in SF-8 survey scores between these groups.The COSS questionnaire is a novel survey instrument to measure obstructive sialadenitis symptom severity that could be helpful in defining outcomes of SASDS. COSS scores under 10 correlate with complete resolution of symptoms, whereas scores between 10 and 25 correlate with partial resolution.

Abstract Background Factors associated with disease‐free survival (DFS) after salvage therapy for recurrent oropharyngeal squamous cell carcinoma (SCC) in the context of human papillomavirus (HPV) are poorly understood. Methods A retrospective cohort analysis was conducted of patients with recurrent oropharyngeal SCC with known HPV tumor status who received salvage therapy. Results Eighty‐six patients were eligible for analysis. Sixty‐four patients (74%) were HPV‐positive. In multivariable analysis, HPV‐positive tumor status (hazard ratio [HR] = 0.30; 95% confidence interval [CI] = 0.13–0.71; p = .007), clinical response to any salvage therapy (HR = 0.29; 95% CI = 0.11–0.77; p = .01), and surgical salvage (HR = 0.38; 95% CI = 0.16–0.88; p = .02) were associated with improved overall survival (OS). Positive surgical margin was associated with worse DFS after salvage (HR = 8.43; 95% CI = 1.99–35.70; p = .004). Conclusion For recurrent oropharyngeal SCC, HPV‐positive tumor status, surgical salvage, and clinical response to salvage therapy are independently associated with improved OS, but not DFS after salvage. Surgical margin is the only independent predictor of DFS. © 2015 Wiley Periodicals, Inc. Head Neck 38 : E1501–E1509, 2016

The incidence of oropharyngeal carcinoma, involving palatine and lingual tonsils, is increasing globally. This significant rise is driven by human papillomavirus. Whether palatine tonsillectomy affects risk of diagnosis with oropharyngeal carcinoma is unknown. The association between tonsillectomy and incidence of oropharyngeal carcinoma was explored in the Danish Cancer Registry. The association between tonsillectomy and oropharyngeal carcinoma was analyzed by time since first registration of tonsillectomy. Tonsillectomy was a time-dependent variable. Individuals were censored for death, emigration, or tonsillectomy within incident year of diagnosis. Incidence rate ratios (RR) were estimated by Poisson regression models and adjusted for confounders. Kaplan-Meier survival analyses were compared by the log-rank test, and HRs were estimated by Cox proportional hazards models. From 1977 to 2012, the incidence of tonsillectomies significantly decreased, whereas the incidence of oropharyngeal carcinoma significantly increased. Tonsillectomy was not associated with risk of oropharyngeal carcinoma or malignancies of other anatomic sites, including base of tongue. However, tonsillectomy significantly reduced risk of diagnosis with tonsil carcinoma [RR, 0.40; 95% confidence interval (CI), 0.22-0.70]. The risk of diagnosis with tonsil carcinoma at age <60 years was significantly decreased (RRadj, 0.15; 95% CI, 0.06-0.41) after tonsillectomy. Tonsillectomy within 1 year of diagnosis with tonsil carcinoma was associated with significantly improved overall survival (HR, 0.53; 95% CI, 0.38-0.74). In conclusion, remote history of tonsillectomy reduces the risk of diagnosis with tonsil carcinoma. These data inform risk and benefit of tonsillectomy, a common procedure and design of secondary prevention trials.

The treatment of oropharyngeal cancer has undergone a paradigm shift in the past 2 decades, with an increase in the use of nonoperative treatment owing to poor functional outcomes associated with traditional surgical approaches. Transoral robotic surgery (TORS) allows surgical resection of oropharyngeal cancer (OPC) with less morbidity through a minimally invasive approach.To investigate the relationship among TORS and short- and long-term outcomes and costs in surgically treated patients with OPC.Retrospective cross-sectional analysis of 3573 patients who underwent an ablative procedure for OPC in 2010 to 2012 using the MarketScan Commercial Claim and Encounters database.The association between TORS and short- and long-term outcomes, length of hospitalization, and treatment-related costs was analyzed using descriptive statistics and multivariate regression modeling.Transoral robotic surgery was performed in 304 surgical cases (8.5%); 94.7% of patients were 40 to 64 years old, and 70.7% were male. The use of TORS increased from 4.1% of surgical cases in 2010 to 13.2% of surgical cases in 2012. Patients who underwent TORS had a lower rate of tracheotomy during treatment (3.9% vs 11.4%), and posttreatment gastrostomy tube use (21.9% vs 34.2%), compared with patients undergoing non-TORS procedures. On multivariate analysis, TORS was not associated with significant differences in postoperative complications or length of hospitalization. There was no significant difference in the odds of receiving postoperative radiation therapy between patients who underwent TORS and those who did not; however, among patients receiving radiation therapy, chemoradiation was significantly less likely following TORS (odds ratio [OR], 0.52; 95% CI, 0.29-0.90). TORS was associated with significantly decreased odds of posttreatment gastrostomy (OR, 0.54; 95% CI. 0.30-0.95) and tracheostomy during treatment (OR, 0.17; 95% CI, 0.06-0.55) at 1 year, and was associated with significantly decreased overall treatment-related costs of care (mean incremental cost, -$22 724).The use of TORS for surgical resection of OPC is increasing in the United States and is associated with significantly lower use of adjuvant chemoradiation, late gastrostomy and tracheostomy dependence, and lower overall treatment-related costs of care. These data have implications for discussions of value in OPC care at a time of health care reform.

Objectives/Hypothesis To examine associations between treatment and volume with survival and costs in elderly patients with laryngeal squamous cell cancer (SCCA). Study Design Retrospective cross‐sectional analysis of Surveillance, Epidemiology, and End Results–Medicare data. Methods We evaluated 2,370 patients diagnosed with laryngeal SCCA from 2004 to 2007 using cross‐tabulations, multivariate logistic and generalized linear regression modeling, and survival analysis. Results Chemoradiation was significantly associated with supraglottic tumors (relative risk ratio: 2.6, 95% confidence interval [CI]: 1.7‐4.0), additional cancer‐directed treatment (odds ratio [OR]: 1.8, 95% CI: 1.2‐2.7), and a reduced likelihood of surgical salvage (OR: 0.3, 95% CI: 0.2‐0.6). Surgery with postoperative radiation was associated with significantly improved survival (hazard ratio [HR]: 0.7, 95% CI: 0.6‐0.9), after controlling for patient and tumor variables including salvage. High‐volume care was not associated with survival for nonoperative treatment but was associated with improved survival (HR: 0.7, 95% CI: 0.5‐0.8) among surgical patients. Initial treatment and 5‐year overall costs for chemoradiation were higher than for all other treatment categories. High‐volume care was associated with significantly lower costs of care for surgical patients but was not associated with differences in costs of care for nonoperative treatment. Conclusions Chemoradiation in elderly patients with laryngeal cancer was associated with increased costs, additional cancer‐directed treatment, and a reduced likelihood of surgical salvage. Surgery with postoperative radiation was associated with improved survival in this cohort, and high‐volume hospital surgical care was associated with improved survival and lower costs. These findings have implications for improving the quality of laryngeal cancer treatment at a time of both rapid growth in the elderly population and diminishing healthcare resources. Level of Evidence 2c Laryngoscope , 124:1827–1835, 2014

Objectives/Hypothesis To examine associations between pretreatment variables, short‐term and long‐term swallowing and airway impairment, and survival in elderly patients treated for laryngeal squamous cell cancer (SCCA). Study Design Retrospective analysis of Surveillance, Epidemiology, and End Results‐Medicare data. Methods Longitudinal data from 2,370 patients diagnosed with laryngeal SCCA from 2004 to 2007 were evaluated using cross‐tabulations, multivariate logistic regression, and survival analysis. Results Dysphagia (odds ratio [OR] = 1.5 [1.2–1.7]), weight loss (OR = 1.3 [1.1–1.6]), esophageal stricture (OR = 3.8 [2.5–5.9]), airway obstruction (OR = 1.9, [1.6–2.3]), tracheostomy (OR = 1.5 [1.2–1.9]), and pneumonia (OR = 1.8 [1.4–2.2]) increased 1 year after treatment. The odds of airway obstruction, esophageal stricture, and pneumonia increased over subsequent years, with significantly increased risk at 5 years for airway obstruction (OR = 3.3 [1.8–5.8]) and pneumonia (OR = 5.2 [2.5–10.7]). Pretreatment dysphagia, chemoradiation, and salvage surgery were significant predictors of long‐term dysphagia, weight loss, tracheostomy, and gastrostomy, with pretreatment dysphagia and salvage surgery also associated with pneumonia. Surgery and postoperative radiation was associated with long‐term dysphagia (OR = 1.4 [1.0–1.9]) but reduced odds of long‐term pneumonia (OR = 0.7 [0.5–0.9]). Long‐term dysphagia, gastrostomy or tracheostomy dependence, weight loss, airway obstruction, and pneumonia were associated with poorer survival, with pneumonia associated with the greatest risk of death at 5 years (hazard ratio = 2.6 [2.4–2.9]). Conclusions Airway and swallowing impairment is common after laryngeal SCCA treatment in elderly patients, increases over time, and is associated with poorer survival—with pneumonia associated with the highest risk of long‐term mortality. Patients with pretreatment dysphagia, initial treatment with chemoradiation, and salvage surgery represent a high‐risk group with an increased risk of disability and death. Level of Evidence 2c. Laryngoscope , 125:924–933, 2015

To examine the cumulative effect of diagnostic steps for primary tumor identification in patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP), including lingual tonsillectomy, and the impact of primary tumor identification on subsequent treatment.Retrospective analysis.We reviewed the records of 110 patients diagnosed with HNSCCUP between 2003 and 2015. Results of diagnostic imaging (fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET/CT]), tumor detection with direct laryngoscopy with biopsies, palatine tonsillectomy, and transoral robotic surgery (TORS) lingual tonsillectomy were recorded. Associations between demographic and treatment variables with overall survival (OS) and progression-free survival (PFS) were modeled with Cox proportional hazards models.FDG-PET/CT was suspicious for a primary site in 23/77 (30%) patients. Direct laryngoscopy identified a primary tumor in 34/110 patients (31%). Forty-seven patients underwent palatine tonsillectomy, which identified 17 primaries (36%), yielding a cumulative primary tumor identification of 51/110 (46%). Fourteen patients underwent TORS lingual tonsillectomy, which identified eight primaries (57%), resulting in a cumulative identification of 59/110 (53%). The detection rate increased from 28/63 (44%) to 31/47 (66%) after the addition of TORS lingual tonsillectomy to our institutional approach. Detection rates varied by HPV status. Primary tumor identification altered subsequent radiation planning, as patients with an identified primary tumor received radiation to a smaller volume of tissue than did those without an identified primary tumor. However, there was no significant association between primary tumor identification and OS or PFS.A stepwise approach to primary tumor identification identifies a primary tumor in a majority of patients.4 Laryngoscope, 129:1610-1616, 2019.

The increasing incidence of human papillomavirus (HPV)-related head and neck cancer (HNC) has led to the increasing prevalence of survivors, yet to the best of the authors' knowledge the prevalence of comorbidities during the survivorship period and their effects on survival are relatively unknown.In this retrospective cross-sectional study, individuals with a first incident primary diagnosis of HNC from 2004 through 2011 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked databases were included in the analysis and classified as patients with HPV-related or HPV-unrelated HNC. The presence of 30 comorbid conditions of interest was identified. Associations between comorbidity and treatment group as well as overall survival were evaluated.The study population consisted of 8025 patients with HPV-unrelated HNC and 2499 patients with HPV-related HNC. Hypertension, congestive heart failure, cerebrovascular disease, and chronic obstructive pulmonary disease all were found to be highly prevalent at the time of the cancer diagnosis and increased over time for both groups. These comorbidities were found at significantly lower rates in the HPV-related HNC population, yet were associated with an increased risk of death in both groups. The probabilities of developing cancer-related comorbidities such as pneumonia, dysphagia, weight loss, malnutrition, and dental issues rose significantly in both groups after treatment but were more likely in patients with HPV-related HNC. In both groups of patients, the presence of each comorbidity either at the time of diagnosis or during survivorship was associated with a significantly increased risk of death.There is a large burden of comorbidities in both patients with HPV-related and HPV-unrelated HNC, both of which are associated with decreased survival. Oncologic surveillance should not be limited to the evaluation of disease status, but also should include screening for the highly prevalent conditions associated with the risk of death.

Abstract Background Postoperative radioactive iodine (RAI) administration is widely utilized in patients with differentiated thyroid cancer. While beneficial in select patients, it is critical to recognize the potential negative sequelae of this treatment. The prevention, diagnosis, and management of the salivary and lacrimal complications of RAI exposure are addressed in this consensus statement. Methods A multidisciplinary panel of experts was convened under the auspices of the American Head and Neck Society Endocrine Surgery and Salivary Gland Sections. Following a comprehensive literature review to assess the current best evidence, this group developed six relevant consensus recommendations. Results Consensus recommendations on RAI were made in the areas of patient assessment, optimal utilization, complication prevention, and complication management. Conclusion Salivary and lacrimal complications secondary to RAI exposure are common and need to be weighed when considering its use. The recommendations included in this statement provide direction for approaches to minimize and manage these complications.

To determine the effect of tracheotomy on polysomnographic and arterial blood gas data in patients with obstructive sleep apnea (OSA).A retrospective study of all patients who underwent tracheotomy and were studied polysomnographically at the Johns Hopkins Sleep Disorders Center, Baltimore, Md, since 1981.A regional sleep disorders center.Twenty-eight patients (8 women and 20 men), aged 22 through 77 years. Patients were categorized into 2 groups on the basis of whether they had already undergone tracheotomy before polysomnography. Group 1 patients all had a polysomnographic diagnosis of OSA before tracheotomy. They were further subdivided on the basis of whether cardiopulmonary decompensation had been absent (group 1a, n=10) or present (group 1b, n=13). Group 2 patients (n=5) had undergone tracheotomy to treat upper airway obstruction that developed after non-apnea-related upper aerodigestive tract surgeries.Tracheotomy.Nocturnal non-rapid eye movement, apnea-hypopnea index, percentage oxyhemoglobin saturation, and arterial blood gas data.Patients with OSA underwent tracheotomy as definitive treatment for the apnea (n=15), to prevent postoperative upper airway compromise after uvulopalatopharyngoplasty (n=7), and to treat upper airway compromise after non-apnea-related upper aerodigestive tract surgeries (n=6). Tracheotomy alleviated apnea in all 10 patients with uncomplicated sleep apnea (group 1a). For patients with OSA complicated by cardiopulmonary decompensation (group 1b), tracheotomy improved but did not eliminate sleep apnea in 7 of the 13 patients, despite overall improvement in arterial blood gas values. For patients whose sleep apnea had not been diagnosed polysomnographically before tracheotomy (group 2), tracheotomy was still required to treat OSA that had previously not been recognized.Tracheotomy effectively treated patients with uncomplicated OSA, but was much less effective in treating patients with OSA and cardiopulmonary decompensation. In patients who underwent tracheotomy in conjunction with other upper aerodigestive tract surgeries, concomitant obstructive sleep apnea often required continued use of a tracheotomy to maintain upper airway patency.