James L. Netterville

Increased Epidermal Growth Factor Receptor Gene Copy Number Is Associated With Poor Prognosis in Head and Neck Squamous Cell Carcinomas

PURPOSE High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR pathway may improve the use of EGFR inhibitors in HNSCC. PATIENTS AND METHODS EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points. RESULTS Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were found. However, the FISH-positive group was associated with worse progression-free and overall survival (P < .05 and P < .01, respectively; log-rank test). When microarray data were interrogated using the FISH results as a supervising parameter, ECop (which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity) had higher expression in FISH-positive tumors. CONCLUSION High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.

Gene Expression Differences Associated with Human Papillomavirus Status in Head and Neck Squamous Cell Carcinoma

Human papillomavirus (HPV) is associated with a subset of head and neck squamous cell carcinoma (HNSCC). Between 15% and 35% of HNSCCs harbor HPV DNA. Demographic and exposure differences between HPV-positive (HPV+) and negative (HPV−) HNSCCs suggest that HPV+ tumors may constitute a subclass with different biology, whereas clinical differences have also been observed. Gene expression profiles of HPV+ and HPV− tumors were compared with further exploration of the biological effect of HPV in HNSCC. Thirty-six HNSCC tumors were analyzed using Affymetrix Human 133U Plus 2.0 GeneChip and for HPV by PCR and real-time PCR. Eight of 36 (22%) tumors were positive for HPV subtype 16. Statistical analysis using Significance Analysis of Microarrays based on HPV status as a supervising variable resulted in a list of 91 genes that were differentially expressed with statistical significance. Results for a subset of these genes were verified by real-time PCR. Genes highly expressed in HPV+ samples included cell cycle regulators (p16INK4A, p18, and CDC7) and transcription factors (TAF7L, RFC4, RPA2, and TFDP2). The microarray data were also investigated by mapping genes by chromosomal location (DIGMAP). A large number of genes on chromosome 3q24-qter had high levels of expression in HPV+ tumors. Further investigation of differentially expressed genes may reveal the unique pathways in HPV+ tumors that may explain the different natural history and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HNSCC treatment.

Silastic medialization and arytenoid adduction : the Vanderbilt experience : a review of 116 phonosurgical procedures

From April 1987 to April 1992, 116 phonosurgical procedures were performed to treat glottal incompetence. The initial numbers of these surgical procedures included the following: 29 primary Silastic medializations, 3 primary Silastic medializations with arytenoid adduction, 53 secondary Silastic medializations, 4 secondary Silastic medializations with arytenoid adduction, and 11 bilateral Silastic medializations. These procedures are useful in treating unilateral true vocal cord paralysis, scarring, bowing, or paresis, as well as bilateral true vocal cord bowing. Of the initial 100 patients, 16 later underwent a revision with either a larger implants being placed or an arytenoid adduction. Primary Silastic medialization is the placement of an implant under general anesthesia in the same surgical setting in which laryngeal innervation is sacrificed. Secondary Silastic medialization is the placement of an implant under local anesthesia for a preexistent vocal cord malfunction. In either case, overall voice results for unilateral paralysis are very good. Primary Silastic medialization significantly decreases the postoperative rehabilitation period in skull base patients because of the immediate postoperative glottal competence and decreased use of perioperative tracheotomy. Bilateral implants yielded good results in 6 patients with presbylaryngis, but 6 other patients with bowing from other causes experienced only moderate improvement in speech quality. There were no implant extrusions; however, 1 implant was removed secondary to a persistent laryngocutaneous fistula in a patient who had previously undergone laryngeal irradiation. This was the only complication in this series.

Implications of Follicular Neoplasms, Atypia, and Lesions Suspicious for Malignancy Diagnosed by Fine-Needle Aspiration of Thyroid Nodules

ObjectiveTo break out subcategories of atypical and suspicious cytologic interpretations of thyroid aspirations and correlate those with final histologic diagnosis. Summary Background DataFine-needle aspiration (FNA) of thyroid nodules has become the primary diagnostic tool in the initial evaluation of thyroid nodules. Management of thyroid nodules is based on statistical data correlating a specific cytologic reading with the probability of malignancy. Two particular cytologic readings that frustrate both cytopathologists and surgeons are follicular neoplasms and cells that show atypia. In most reported series, follicular neoplasms and cells showing atypia are included in a broad “suspicious” category, with reported overall malignancy rates generally between 20% and 30%. However, there is interest in determining whether these suspicious lesions can be subcategorized, allowing a more accurate assessment of the risk of malignancy. In addition, there is recent evidence that the incidence of follicular cancer may be declining in this country, possibly decreasing the probability that a “follicular neoplasm” will prove to be a follicular cancer. MethodsFrom January 1994 through December 2000, 709 thyroid FNAs were performed at a single institution. Those interpreted as suspicious and the subsequent histologic reports were reviewed. From this set, four specific categories were defined, and the clinical records for patients whose cytology matched these categories form the subject of this study. These four categories are follicular neoplasms without atypia, follicular neoplasms with atypia, atypia, and suspicious for malignancy. In addition, lesions with nondiagnostic cytology were reviewed. Only lesions for which there was histologic follow-up were considered. ResultsNinety-eight aspirates were categorized as follicular neoplasms without atypia, follicular neoplasms with atypia, or atypia alone. Of 74 follicular neoplasms without atypia, only 5 (6.8%) were malignant, and none of these were follicular thyroid cancers. Nine of the lesions were follicular neoplasms with atypia, and four (44.4%) of these were malignant, including two that were invasive follicular cancers. Of 15 lesions showing atypia alone, 3 (20%) were malignant, all of which were papillary thyroid cancers. Twenty-five additional patients had lesions highly suspicious for malignancy. Twenty-one (84%) of these lesions were malignant, the majority being papillary thyroid cancers. Only one was a follicular cancer. Fifty patients with nondiagnostic cytology had subsequent action taken. Thirty-one of these lesions were resected, with five (16.1%) proving to be malignant. ConclusionsThyroid nodules whose FNA is diagnosed as highly suspicious for malignancy should be resected unless there are significant contraindications to a surgical procedure. The extremely low rate (2%) of invasive follicular cancers among all follicular neoplasms may reflect changing histologic criteria for follicular carcinoma, a true change in the disease frequency, or both. For thyroid nodules whose cytology shows a follicular neoplasm without atypia, malignancy rates of 8% or less may allow nonsurgical options, including reevaluation in selected populations. Continued efforts to correlate malignancy rates to specific cytologic criteria will allow patients to make more informed decisions regarding their medical care.

Clinical practice guideline: Tympanostomy tubes in children

Objective Insertion of tympanostomy tubes is the most common ambulatory surgery performed on children in the United States. Tympanostomy tubes are most often inserted because of persistent middle ear fluid, frequent ear infections, or ear infections that persist after antibiotic therapy. Despite the frequency of tympanostomy tube insertion, there are currently no clinical practice guidelines in the United States that address specific indications for surgery. This guideline is intended for any clinician involved in managing children, aged 6 months to 12 years, with tympanostomy tubes or being considered for tympanostomy tubes in any care setting, as an intervention for otitis media of any type. Purpose The primary purpose of this clinical practice guideline is to provide clinicians with evidence-based recommendations on patient selection and surgical indications for and management of tympanostomy tubes in children. The development group broadly discussed indications for tube placement, perioperative management, care of children with indwelling tubes, and outcomes of tympanostomy tube surgery. Given the lack of current published guidance on surgical indications, the group focused on situations in which tube insertion would be optional, recommended, or not recommended. Additional emphasis was placed on opportunities for quality improvement, particularly regarding shared decision making and care of children with existing tubes. Action Statements The development group made a strong recommendation that clinicians should prescribe topical antibiotic eardrops only, without oral antibiotics, for children with uncomplicated acute tympanostomy tube otorrhea. The panel made recommendations that (1) clinicians should not perform tympanostomy tube insertion in children with a single episode of otitis media with effusion (OME) of less than 3 months’ duration; (2) clinicians should obtain an age-appropriate hearing test if OME persists for 3 months or longer (chronic OME) or prior to surgery when a child becomes a candidate for tympanostomy tube insertion; (3) clinicians should offer bilateral tympanostomy tube insertion to children with bilateral OME for 3 months or longer (chronic OME) and documented hearing difficulties; (4) clinicians should reevaluate, at 3- to 6-month intervals, children with chronic OME who did not receive tympanostomy tubes until the effusion is no longer present, significant hearing loss is detected, or structural abnormalities of the tympanic membrane or middle ear are suspected; (5) clinicians should not perform tympanostomy tube insertion in children with recurrent acute otitis media (AOM) who do not have middle ear effusion in either ear at the time of assessment for tube candidacy; (6) clinicians should offer bilateral tympanostomy tube insertion to children with recurrent AOM who have unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy; (7) clinicians should determine if a child with recurrent AOM or with OME of any duration is at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors; (8) in the perioperative period, clinicians should educate caregivers of children with tympanostomy tubes regarding the expected duration of tube function, recommended follow-up schedule, and detection of complications; (9) clinicians should not encourage routine, prophylactic water precautions (use of earplugs, headbands; avoidance of swimming or water sports) for children with tympanostomy tubes. The development group provided the following options: (1) clinicians may perform tympanostomy tube insertion in children with unilateral or bilateral OME for 3 months or longer (chronic OME) and symptoms that are likely attributable to OME including, but not limited to, vestibular problems, poor school performance, behavioral problems, ear discomfort, or reduced quality of life and (2) clinicians may perform tympanostomy tube insertion in at-risk children with unilateral or bilateral OME that is unlikely to resolve quickly as reflected by a type B (flat) tympanogram or persistence of effusion for 3 months or longer (chronic OME).

Carotid body tumors: A review of 30 patients with 46 tumors

Minimal morbidity occurs with resection of most carotid body tumors (CBT). With larger tumors significant injury to the cranial nerves has been reported. In order to assess the operative sequelae rate, 30 patients with CBT were reviewed. Sixteen patients either presented with bilateral carotid body tumors or had previously undergone a resection of the contralateral carotid body tumors, for a total carotid body tumor count of 46. Sixteen patients demonstrated a familial pattern while 14 were nonfamilial. Within the familial group, 14 of 16 presented with multiple paragangliomas as compared to 6 of 14 in the nonfamilial group. Tumor size ranged from 0.8 to 12 cm. Vascular replacement occurred in 2 of 20 patients with tumors <5.0 cm, compared with 5 of 9 with tumors >5.0 cm. Four patients lost cranial nerves with the resection: superior laryngeal nerve (SLN), 4; cranial nerve X, 1; cranial nerve XII, 1. Ten patients developed baroreceptor failure secondary to bilateral loss of carotid sinus function. First‐bite pain occurred in 10 of 25 operative patients. Cranial nerve loss can be minimal with resection of carotid body tumors, however, baroreceptor failure and first‐bite pain are postoperative sequelae that are often disregarded in the postoperative period.

BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors

UNLABELLED Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAF(L597R) mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF(V600) mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAF(L597) mutations in melanoma. SIGNIFICANCE This study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAF(L597R)-mutant melanoma.

Vocal Fold Paralysis following the Anterior Approach to the Cervical Spine

The anterior cervical approach is commonly used for access to the cervical spine. Vocal fold paralysis (VFP), a complication of this approach, is underrepresented in the literature. A review of the database of the Vanderbilt Voice Center revealed 289 patients with VFP, including 16 patients who developed paralysis as a result of an anterior cervical approach. The paralysis was on the right side in all but 1 patient. Compared to patients who developed VFP after thyroidectomy and carotid endarterectomy, patients with VFP after an anterior cervical approach have a higher incidence of aspiration and dysphagia, suggesting the presence of trauma to the superior laryngeal and pharyngeal branches as well as the recurrent branch of the vagus nerve. Two patients had partial return and 1 patient had complete return of vocal fold movement within 10 months. Of the remaining 13 patients, 8 underwent vocal fold medialization with improvement of symptoms. Two patients are 6 and 7 months postinjury and await vocal fold medialization. Two patients are 27 months and 45 months postinjury and are considering vocal fold medialization. The remaining patient was lost to follow-up. An anatomic-geometric analysis of the right and left recurrent laryngeal nerves was performed by using measurements obtained from computed tomography scans of 8 patients with idiopathic unilateral VFP, as well as experience gained through surgical and cadaveric dissections. We conclude 1) the anterior cervical approach may place multiple branches of the vagus nerve at risk; 2) because of anatomic-geometric factors, die right-sided anterior cervical approach may carry a greater risk to the ipsilateral recurrent laryngeal nerve than does the left; and 3) an understanding of the anatomy and geometry presented herein allows relatively safe exposure from either side of the neck.

Quality-of-life assessment in patients with unilateral vocal cord paralysis

OBJECTIVE: Our objective was to identify the impact of unilateral vocal cord paralysis (UVCP) on an individuals quality of life both before and after thyroplasty. STUDY DESIGN AND SETTING: This was a prospective observational outcome study of consecutive patients presenting to a laryngology clinic with UVCP. Participants received The Medical Outcomes Study Short Form 36-Item Health Survey (SF-36), the Voice Handicap Index (VHI), and the Voice Outcome Survey (VOS). Patients underwent medialization laryngoplasty with silastic, with or without arytenoid adduction. Outcome measures were repeated after surgery. RESULTS: A review of 45 patients at presentation revealed statistically significant reductions in quality of life as measured by each survey. Marked improvements were noted after surgery. CONCLUSIONS: Our preoperative data support a profile of significant general health-related and voice-related limitations caused by UVCP. Patient perceptions improved significantly after the surgical treatment of glottal insufficiency. SIGNIFICANCE: The SF-36, VHI, and VOS provide an important complement to traditional endpoints in the analysis of patients with UVCP.

Management of substernal goiter.

Objective: To analyze the presentation, evaluation and treatment of patients with large substernal goiters, with emphasis on the radiographic evaluation and the results of treatment. Study Design: A retrospective chart review of 150 patients undergoing thyroidectomy at the Vanderbilt University Department of Otolaryngology—Head and Neck Surgery. Methods: Charts of patients undergoing thyroidectomy were reviewed. Those with substernal goiter, defined as a major portion of the goiter within the mediastinum, were included in the study. When available, the radiographic studies were reviewed by a staff neuroradiologist. Results: Twenty‐three patients (15.3%) presented with substernal extension of the goiter. Characteristics of these patients included mean age of 59 years, 78% female, symptoms of compression such as dyspnea, choking, and dysphagia (65%), hoarseness (43%), and previous thyroid surgery (30%). Seventeen percent were asymptomatic. Preoperative radiographs demonstrated tracheal compression (73%), tracheal deviation (77%), esophageal compression (27%), and major vessel displacement (50%). Histology revealed multinodular goiter (16/23, 70%), thyroiditis (3/23, 13%), and malignancy (4/23, 17%). The average size of the resected specimen in greatest dimension was 8.0 cm (range, 3.0–14.0 cm) and weighed 148 g (range, 39–426 g). All were successfully approached through a transcervical incision without the need for sternotomy, and total thyroidectomy was performed in 83% of the cases. No major complications have been documented, and no evidence of tracheomalacia was encountered. Conclusion: Despite the large size of these goiters and the significant involvement of the major mediastinal structures, all were approached through the transcervical incision. Further, despite significant tracheal involvement, there were no cases of tracheomalacia or major complications. For intraoperative planning, the authors advocate the routine use of preoperative computed tomography scanning. Laryngoscope, 108:1611–1617, 1998