It is not just IMRT: Human papillomavirus related oropharynx squamous cell carcinoma is associated with better swallowing outcomes after definitive chemoradiotherapy.

OBJECTIVES: Long term swallowing dysfunction in patients with oropharynx squamous cell carcinoma (OPSCC) treated with concurrent chemoradiation (CRT) is declining. While the use of intensity modulated radiotherapy (IMRT) is commonly believed to be a potential cause, we hypothesize that the increasing incidence of human papillomavirus (HPV) related disease may also favorably impact this outcome. MATERIALS AND METHODS: We reviewed 130 HPV+ and 17 HPV- patients with stage III-IV OPSCC treated exclusively with conventional 3-field radiotherapy with chemotherapy between 2002 and 2010. The rates of normal diet, limited diet (significant restrictions in the types of foods eaten, and/or requiring nutritional supplementation for weight maintenance) and feeding tube dependence (FTD) were compared between HPV+ and HPV- patients. Cox proportional hazards modeling were used to perform univariate analysis (UVA) to examine predictors of a combined endpoint of dietary limitation, which included limited diet and/or FTD. These outcomes were also compared to our previously reported cohort of OPSCC patients treated between 1989 and 2002 to assess changes in toxicity over time given the changing disease epidemiology, in the setting of identical treatment regimens. RESULTS: With a median follow-up of 55 months, HPV+ patients more frequently had resumed a normal diet (87% vs. 65%) at last follow up and had lower rates of limited diet (9% vs. 18%) and FTD (4% vs. 18%) compared to HPV- patients (p=0.02). HPV status was the only significant predictor of reduced swallowing dysfunction on UVA (HR 0.19; p=0.008). When compared to our 1989-2002 cohort, patients treated between 2002 and 2010 had less FTD (7.5% vs. 34%, p<0.001) and dietary limitations (26% vs.46%, p<0.001) at 6 months post treatment. CONCLUSIONS: HPV+ patients with OPSCC have reduced late swallowing dysfunction after chemoradiation compared to HPV- patients. The changing epidemiology of OPSCC may play a role in toxicity reduction in these patients, independent of the increasing use of IMRT.

Microsatellite mutations in buccal cells are associated with aging and head and neck carcinoma.

Carcinogen exposure from tobacco smoking is the major cause of upper aerodigestive tract cancer, yet heavy smokers only have about a 10% life-time risk of developing one of these cancers. Current technologies allow only limited prediction of cancer risk and there are no approved screening methods applicable to the general population. We developed a method to assess somatic mutational load using small-pool PCR (SP-PCR) and analysed mutations in DNA isolated from cells obtained by mouth rinse. Mutation levels in the hypermutable tetranucleotide marker D7S1482 were analysed in specimens from 25 head and neck squamous carcinoma (HNSCC) cases and 31 controls and tested for associations with age, smoking history and cancer status. We found a significant association between mutation frequency and age (P=0.021, Generalized Linear Model (GLM), N=56), but no influence of smoking history. Cases had higher mutation frequencies than controls when corrected for the effects of age, a difference that was statistically significant in the subgroup of 10 HNSCC patients who were treated with surgery only (P=0.017, GLM, N=41). We also present evidence that cancer status is linked to levels of nonunique, and presumably clonally derived, mutations in D7S1482. Insertion mutations were observed in 833 (79%) of 1058 alleles, of which 457 (43%) could be explained by insertion of a single repeat unit; deletion mutations were found in 225 (21%) of tested alleles. In conclusion, we demonstrate that the sensitive detection of single molecule mutations in clinical specimens is feasible by SP-PCR. Our study confirms an earlier report that microsatellite mutations increase with age and is the first to provide evidence that these mutations may be associated with cancer status in individual subjects.

Increasing use of the scapula osteocutaneous free flap.

OBJECTIVES: To determine the appropriate use of the scapula osteocutaneous free flap (SOFF) and to document donor site morbidity. STUDY DESIGN: Retrospective review and prospective physical therapy evaluation. METHODS: A computer database of all free flap procedures performed at a single institution was created. Specific clinical and operative details from cases involving a bone flap were extracted from the database. Rates of usage of the various osteocutaneous flaps were compared over four successive 2-year intervals (1992-1999). A single physical therapist performed a structured evaluation of the donor site. RESULTS: Overall, 64 bone flap procedures were performed, of which 24 (37.5%) were SOFF procedures. The SOFF utilization has increased from 6.6% to 63.6%, while fibula and iliac crest utilization has fallen significantly. This is in part because of the greater versatility of the SOFF, with the possibility of separate skin paddles and adequate bone length. The mean cutaneous area harvested with the SOFF was 110 cm2 (range, 48-200 cm2) compared with 55.4 cm2 (range, 25-102 cm2) and 77.6 cm2 (range, 50-120 cm2) for the fibula and iliac crest, respectively. Mean bone flap lengths were 8.37, 7.65, and 10.1 cm, respectively, for the SOFF, fibula, and iliac crest. Dual skin paddles were used in 50% of the SOFF procedures versus 2.8% for the fibula flap procedures. There were no significant complications of the donor site in any patient, and there was only one flap failure (4.1%). Related to the SOFF, donor site morbidity was subjectively judged as "mild," for pain, mobility, and strength. There were no complaints of poor appearance of the donor site. Activities of daily living were judged as "not limited" or 'limited a little" in the majority of patients. Objective measurements of range of motion revealed an average reduction of 1 degree to 12 degrees in five different shoulder functions. Elbow and arm ranges of motion were not limited. Strength was minimally reduced in the shoulder, while the arm and forearm showed no reduction in strength. CONCLUSIONS: The SOFF is a versatile osteocutaneous free flap that can be used for a multitude of reconstructive problems. This and its relative lack of significant donor site morbidity have caused its use to increase significantly.

Tongue replantation in an animal model.

Although the tongue is not a vital organ in sustaining life, it may be a vital organ in sustaining the will to live in many people. As carcinoma of the tongue represents the majority of the 30,000 oral cavity cancers diagnosed per year in the United States, many patients face the potential consequences of resection of part or all of the tongue for cure. To date, reconstructive options do not restore optimal tongue function including articulation, swallowing, taste, or sensation. With the ultimate goal of improving tongue reconstruction, we report on a successfully performed autograft transplantation of the tongue in an animal model. Before undertaking allograft transplantation of the tongue, an autograft tongue transplant would be attempted to identify the feasibility of such a procedure and to determine the similarity of an animal model with human techniques. The dog's neck, tongue, and oral anatomy represent an excellent animal model for tongue reconstruction. This procedure can be performed successfully in an animal model. The only previously published replantation of the tongue involved the reattachment of the anterior portion of a human tongue after physical trauma. To our knowledge, the enclosed report represents the first successful total excision and replantation of the tongue in either a human or animal model.

Long-standing lateral neck mass as the initial manifestation of well-differentiated thyroid carcinoma.

OBJECTIVE: To analyze the presentation, evaluation, and treatment of a subset of patients with well-differentiated thyroid carcinoma who present with a lateral neck mass and no palpable disease in the thyroid gland. STUDY DESIGN: A retrospective review of all patients undergoing thyroidectomy for malignancy. METHODS: A database of all thyroidectomies performed for malignancy by the Vanderbilt University Department of Otolaryngology-Head and Neck Surgery from 1992 to 1997 was created. Patients who presented with an isolated neck mass without evidence of palpable disease in the thyroid were selected for the study population. RESULTS: There were 60 cases of thyroid malignancy, with 14 cases (23.3%) that presented as isolated lateral neck mass. The characteristics of this group (compared with the population of all thyroid malignancies) include younger age at presentation (37.7 +/- 15.2 y vs. 49.8 +/- 15.6 y; Student t test: P = .019) and long-standing presence of symptoms (27.4 +/- 39.6 mo vs. 3.6 +/- 3.9 mo; P = .023). These patients generally presented from a referring facility after having an excisional biopsy, which was 100% accurate. Fine-needle aspiration is becoming more useful and was 66.7% accurate. Histological examination revealed cancer in the thyroid gland in all patients, 11 cases of papillary carcinoma, 2 follicular carcinomas, and one medullary carcinoma The mean size of the primary focus was 10.9 +/- 8.7 mm, with 29% demonstrating bilateral disease and 14% demonstrating multifocal disease in the ipsilateral gland. The neck specimens revealed an average of 5.3 +/- 3.2 metastatic nodes in levels II-IV and 3.9 +/- 4.6 metastatic nodes in the paratracheal region. CONCLUSION: Based on this patient population, the long-standing lateral neck mass in the young patient should raise the physician's index of suspicion for thyroid carcinoma Fine-needle aspiration should be used in conjunction with judicious excisional biopsy. The bilateral and multifocal nature of otherwise occult primary disease argues for total thyroidectomy in this setting.

Current options in management of head and neck cancer patients.

Head and neck cancer, particularly squamous cell carcinoma (SCC) of the upper aerodigestive tract, poses difficult diagnostic and therapeutic challenges to the clinician. A methodical approach, including complete visualization of mucosal surfaces, appropriate imaging, and tissue diagnosis whenever possible, gives patients the best opportunity for early intervention. A treatment program of surgery, radiation, or chemotherapy is best developed by a devoted head and neck oncologic team, involving surgeons, radiation and medical oncologists, and rehabilitative specialists with significant experience in the care of head and neck oncologic patients. Despite new advancements in the treatment of patients with advanced stage SCC of the head and neck, little progress has been made in overall survival. Several new avenues of investigation are currently being explored, one of which may ultimately provide the answer for this devastating disease.

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.

Delayed regional metastasis from midfacial squamous carcinomas.

BACKGROUND: Metastases from mucosal and cutaneous carcinomas can present in a delayed fashion, and this late presentation may confer a different prognosis after conventional treatment. METHODS: We present a series of patients in which there was a significant time delay between the treatment of a squamous carcinoma of the skin or mucosa of the midface and the detection of regional metastases in 12 of the 13 cases. Primary tumors were located on the lower lip and commissure (n = 3), nasal tip (n = 2), nasal ala (n = 1), columella (n = 1), nasofacial crease (n = 2), maxillary alveolus (n = 3), and mandibular alveolus (n = 1). Metastatic spread manifested by palpable perifacial or submandibular lymph nodes was not evident until greater than 11 months after the treatment of the primary site in 12 of 13 patients (range, 3-45 months). Nine of the patients were clinically staged as N1, whereas there was one each in the N2a, N2b, N2c, and N3 categories. Eleven of the 13 patients were initially seen with palpable disease involving the perifacial nodes within or around the submandibular gland. All patients were treated with neck dissection except one, who refused surgical treatment and underwent a second course of radiotherapy to the cervical region. The nine patients initially seen with clinical stage N1 disease underwent neck dissection with preservation of the sternocleidomastoid, internal jugular vein, and accessory nerve. RESULTS: Of 10 patients with perifacial node metastases who underwent neck dissection, 8 required sacrifice of the marginal mandibular nerve and overlying platysma to gain adequate margin. Extracapsular spread was present in 11 patients, (8 of 9 who were clinically N1). Postoperative radiotherapy was recommended to all patients with extracapsular spread, although only 7 of the 11 received radiotherapy. There were no regional recurrences after a minimum follow-up of 1 year (range, 12-65 months; mean, 31.4 months). Histologic grade appeared to have no influence on prognosis. CONCLUSIONS: This cohort demonstrates the ability of midfacial squamous cell carcinoma to manifest regional metastatic disease over a delayed time. This delayed presentation appears to confer a more favorable response to treatment. For midfacial cancers, the perifacial nodes are at greatest risk for metastatic spread. For tumors in this region, primary treatment of the neck is probably not warranted, but careful extended follow-up for the potential of delayed cervical metastasis is prudent.

Sublabial, transseptal, transsphenoidal approach to the pituitary region guided by the ACUSTAR I system.

OBJECTIVE: Advances in imaging resolution have resulted in superior visualization of intracranial anatomy. Because of the inherent complexity of the surgical exposure of these lesions, intraoperative localizing techniques are required. Currently, C-arm fluoroscopy provides only two-dimensional localization for these anatomic structures. The recently described ACUSTAR I system, developed in conjunction with Codman and Shurtleff, Inc. (Randolph, Mass.), is an interactive, image-guided device that allows three-dimensional localization with a degree of accuracy previously unattainable. We assessed the clinical utility of the ACUSTAR I system for intraoperative spatial confirmation during transsphenoidal approaches to pituitary lesions. METHODS: Eight patients underwent transsphenoidal approaches to pituitary lesions with the assistance of the ACUSTAR I system. The spatial relationships were clinically judged intraoperatively by the surgeon and by use of traditional C-arm fluoroscopy and then were compared with the ACUSTAR I system results. RESULTS: In all eight patients, the ACUSTAR I system correctly displayed the surgical orientation and provided localization to within less than 1 mm. In two patients, this facilitated the redirection of an errant approach. No complications were associated with the use of this image-guided device. CONCLUSIONS: The ACUSTAR I system is useful in displaying accurate, three-dimensional anatomic relationships during transsphenoidal approaches to pituitary lesions. This system provides critical information intraoperatively to redirect errant approaches and prevent significant morbidity.

Current concepts in oromandibular reconstruction.

Oromandibular reconstruction represents an exciting and growing area within head and neck reconstructive surgery. The advent and use of free tissue transfer have revolutionized the field. Combining these newer techniques with time-proven techniques presents the reconstructive surgeon with a wide array of reconstructive options in the oromandibular region. This article considers the more common and reliable methods for oromandibular reconstruction. The authors examine the anatomic basis of each option, highlight the literature concerning each technique, and make specific recommendations based on their experience.

Expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases in head and neck squamous cell carcinoma.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes implicated in the invasion and metastasis of many cancers. In situ hybridization techniques were used to reveal sites of expression of collagenase (MMP-1), gelatinase 72 kd (MMP-2), gelatinase 92 kd (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in head and neck carcinomas (N = 21). Both TIMP-1 and gelatinase 72 kd were expressed in nearly all tumors, whereas the expression of collagenase and gelatinase 92 kd showed variability. Tumor-associated expression of MMPs was strongest in stromal cells near advancing margins. No differences in expression levels were detected between primary and metastatic sites. This paper reviews the literature and discusses the significance and possible implications of MMPs in head and neck squamous cell carcinoma.

The effects of 13-cis retinoic acid on squamous cell carcinoma proliferation and adhesion to extracellular matrix proteins.

To understand the role of retinoids in chemoprevention, the authors examined the effects of 13-cis retinoic acid (cRA) on squamous cell carcinoma proliferation and adhesion to extracellular matrix proteins. The antiproliferative effects of cRA were first seen on day 11 (66% inhibition) and progressed through day 19 (96% inhibition). Using an adhesion assay, the authors then investigated the effects of cRA and transforming growth factor-beta1 (TGF-beta1) on cellular adhesion to purified type IV collagen, fibronectin, and laminin matrices. Cells treated for 4 days with TGF-beta1 increased adhesion by 15% to 29%, and cells treated with cRA increased adhesion by 19% to 39%. However, the use of cRA alone resulted in a decrease in adhesion when tumor cells were treated for 7 days (20% to 32%) and 15 days (25% to 40%). The authors also discuss how cRA acts as a differentiating agent on squamous cell carcinoma.

Overview of the rectus abdominis myocutaneous flap in head and neck reconstruction.

The functional and aesthetic consequences of ablative head and neck oncologic surgery pose a significant challenge to the reconstructive surgeon. With the advent of microvascular free tissue transfer the reconstructive capabilities of the surgeon have been greatly expanded. The rectus abdominis musculocutaneous free flap has assumed an important role in contemporary head and neck reconstruction because of its ease of dissection, length and size of the vascular pedicle, convenience of harvest in the supine position, reliability and versatility, and low donor site morbidity.

Other flaps for head and neck use: temporoparietal fascial free flap, lateral arm free flap, omental free flap.

Advances in microvascular surgery have led to the development of new donor sites for head and neck reconstruction. The superficial temporoparietal, lateral arm, and omental free flaps represent three flaps with primarily soft tissue uses. Their reliable blood supply and pliability make them well suited for a variety of head and neck defects. The superficial temporoparietal and lateral arm free flaps may be used as osteocutaneous flaps, but more rarely is this the case. Minimal donor site morbidity is an advantage with the superficial temporoparietal and lateral arm flaps. The morbidity of a laparotomy must be weighed against the advantage gained by employing the omental free flap in cases of soft tissue reconstruction.

Reinnervation of the allograft larynx in the rat laryngeal transplant model.

The rat model for a vascularized laryngeal allograft is duplicated with significant technical modifications. We report the addition of unilateral host-to-allograft recurrent laryngeal nerve anastomosis to this model. Long-term survival experiments determine the feasibility of reinnervation studies of the allograft larynx with this new mode. A total of 59 transplants have been performed on histocompatible Munich Wistar rats, 36 with attempted unilateral allograft reinnervation. Because of the initially high operative mortality rates, additions and modifications of the original technique resulting in reproducibly enhanced survival are detailed. Factors critical to the functional study of this model with regard to reinnervation are elucidated. Preliminary data on allograft reinnervation are reported as confirmed by videodocumentation of vocal fold mobility, evoked and spontaneous electromyography, and glycogen-depletion studies.

Intracavernous carotid pseudoaneurysm after blunt trauma: case report and discussion.

Epistaxis following blunt facial trauma is usually self-limited and arises from the nasal mucosa, sphenopalatine, or anterior ethmoid arteries. Pseudoaneurysm of the intracavernous carotid artery (ICCA) occurs rarely with penetrating facial trauma, but is even more rare following blunt trauma. Rupture carries a greater than 50% mortality. Because rupture usually occurs after several episodes of epistaxis, recognition of subtle historic and physical findings is paramount to optimal management. Once suspicion is raised, definitive diagnosis and treatment is best accomplished with cerebral arteriogram and trapping of the pseudoaneurysm. We have noted that rupture may be precipitated by angiography, and therefore, we advocate availability of emergent and definitive treatment equipment and personnel prior to performing cerebral arteriography. This should include an otolaryngologist, an interventional radiologist, and a neurosurgeon. A case of ICCA pseudoaneurysm is presented, and the key historic factors are discussed. Radiographic diagnosis and management options are discussed.

Endoscopy of nasopharyngeal cancer.

Nasopharyngeal cancer (NPC) is a unique disease with increasing interest for many physicians due to its unusual etiology, histology, and epidemiology. The recent era of fiberoptic endoscopy now provides the clinician with better tools for the screening, diagnosis, staging, and follow-up of NPC. The use of high resolution flexible and rigid nasopharyngoscopy gives the physician an opportunity for a more sensitive examination in a higher proportion of patients. Ultimately, this will allow for earlier diagnosis of NPC, and improved prognosis and better quality of life for the patients with this disease. Also, by allowing the clinician to perform directed biopsies of the nasopharynx under local anesthesia, fiberoptic nasopharyngoscopy allows a less morbid and more cost-effective approach towards this disease, including screening protocols in certain high risk regions of the world.

The platysma myocutaneous flap. Indications and caveats.

The platysma myocutaneous flap has enjoyed limited popularity despite its versatility, dependability, and ease of harvesting. In this article, we describe 12 consecutive patients who underwent platysma flap reconstruction of various oral cavity and oropharyngeal defects. Complications included loss of one skin paddle, one pharyngocutaneous fistula, and one intraoral wound dehiscence. In all patients, bare bone was covered or appropriate spacing between the tongue and other structures was maintained to avoid ankyloglossia. We discuss specific indications and caveats.

Intracellular calcium changes associated with in vitro lymphokine-activated killer and natural killer cell cytotoxicity.

Interleukin 2-activated peripheral blood lymphocytes (lymphokine-activated killer [LAK] cells) have been shown to lyse tumor cells in a nonspecific fashion. Although the mechanisms involved in this cell-mediated lysis are unknown, previous work has shown that T-lymphocyte-mediated cytolysis is associated with massive fluctuations in the intracellular calcium concentration within target cells. Studies were undertaken to determine whether intracellular calcium concentration changes were associated with LAK-mediated cytotoxicity and to determine the effects of calcium channel blockade on in vitro cell-mediated cytotoxicity. Natural killer (NK) and LAK cell cytotoxicity in vitro were measured against head and neck squamous cell carcinoma (UMSCC-11a and UMSCC-38) and Daudi cell lines. Assays were performed in parallel with flow cytometry to measure changes in intracellular calcium concentration within the target cells. Compared with NK cells, LAK cells showed enhanced cytotoxicity against the UMSCC-11a and Daudi lines but not the UMSCC-38 cell line. Both NK and LAK cell cytotoxicity against all the target cell lines directly paralleled significant increases in calcium concentration in the target cells. The addition of verapamil hydrochloride inhibited the rise in intracellular calcium concentration in the sensitive target cells and significantly inhibited both NK and LAK cell cytotoxicity in all the cell lines. The NK cell activity was more sensitive than LAK cell activity to verapamil inhibition. These data suggest that changes in the target cell calcium concentration are early and important events in both NK and LAK cell cytotoxicity in vitro.