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Background and Objective: Fluorescence-guided imaging to assist in identification of malignant margins has the potential to dramatically improve oncologic surgery. However, a standardized method for quantitative assessment of disease-specific fluorescence has not been investigated. Introduced here is a ratiometric threshold derived from mean fluorescent tissue intensity that can be used to semi-quantitatively delineate tumor from normal tissue., Methods: Open-field and a closed-field imaging devices were used to quantify fluorescence in punch biopsy tissues sampled from primary tumors collected during a phase 1 trial evaluating the safety of cetuximab-IRDye800 in patients (n = 11) undergoing surgical intervention for head and neck cancer. Fluorescence ratios were calculated using mean fluorescence intensity (MFI) from punch biopsy normalized by MFI of patient-matched tissues. Ratios were compared to pathological assessment and a ratiometric threshold was established to predict presence of cancer., Results: During open-field imaging using an intraoperative device, the threshold for muscle normalized tumor fluorescence was found to be 2.7, which produced a sensitivity of 90.5% and specificity of 78.6% for delineating disease tissue. The skin-normalized threshold generated greater sensitivity (92.9%) and specificity (81.0%)., Conclusion: Successful implementation of a semi-quantitative threshold can provide a scientific methodology for delineating disease from normal tissue during fluorescence-guided resection of cancer., (© 2015 Wiley Periodicals, Inc.)

An odontogenic myxoma is a rare, benign tumor that is found almost exclusively in the facial bones, usually the mandible. The diagnosis poses a challenge because its features overlap with those of other benign and malignant neoplasms. We present an unusual case of odontogenic myxoma that involved the maxilla, and we review the clinical, radiographic, and histologic characteristics of this case. Even though it is benign, odontogenic myxoma can be locally invasive and cause significant morbidity. Complete surgical excision is the treatment of choice, but it can be challenging because of the tumor's indistinct margins.

Objectives: (1) Investigate overall survival (OS) and disease-free survival (DFS) for high-risk head and neck basal cell carcinoma (HNBCC) requiring large extirpation with free-flap reconstruction. (2) Determine impact of prognostic features-tumor size, subsite, number of high-risk features, perineural invasion, and bony invasion-on high-risk HNBCC survival. (3) Determine survival benefit of adjuvant radiation for high-risk HNBCC., Study Design: Case series with chart review (2002-2013)., Setting: Academic tertiary care center., Subjects and Methods: Consecutive head and neck patients (N = 431) required free-flap reconstruction following tumor extirpation, 38 for aggressive HNBCC. All cases were high risk. DFS and OS were examined using Kaplan-Meier analysis. Prognostic variables and adjuvant radiation were analyzed utilizing Student's t test for continuous variables and Fisher's exact testing for categorical dependent variables. Complications were reported., Results: Mean tumor diameter was 5.17 cm (range, 1.2-15.0 cm). Mean follow-up was 19.9 months. Overall 2-year survival was 80%, falling to 66% at 5 years. Two-year disease-free survival was 72%. Six patients recurred (n = 5 local, 1 distant). Adjuvant radiotherapy improved DFS (P < .01) but not OS (P = .66). Tumors >2.5 cm did not affect OS (P = .61), regardless of subsite. Bone involvement (44.7% cases) did not affect DFS (P = .39) or OS (P = .18)., Conclusions: Larger HNBCC warranting free tissue transfer do not confer worse outcomes, independent of subsite. Adjuvant radiotherapy does not improve OS but significantly affected DFS, allowing for 13.7 additional months of DFS. Bone involvement does not influence DFS or OS and should not preclude surgery, even in advanced cases requiring free-flap reconstruction., (© American Academy of Otolaryngology-Head and Neck Surgery Foundation 2015.)

Objectives/hypothesis: Sentinel lymph node biopsy (SLNB) is considered one of the most important melanoma advancements to date. Since its inception in 1992, a plethora of data and associated controversies has emerged leading to the question: Is SLNB considered the standard of care for head and neck (HN) cutaneous melanoma?, Study Design: English literature (1990-2014) review., Methods: The PubMed database search was conducted using key terms "melanoma" and "sentinel node." This review included both dedicated HN SLNB studies and larger prospective SLNB studies, in which HN patients were included among the cohort. Bibliography cross-referencing was conducted to ensure a comprehensive search., Results: SLNB is safe and accurate in the HN region. Review of large prospective SLNB trials identified the pathologic status of the SLN as the most important prognostic factor for recurrence and survival. Early lymphadenectomy following a positive SLNB imparts a survival benefit., Conclusions: Our review of the current literature suggests that SLNB is the standard of care for selected cases of HN cutaneous melanoma. It is now incorporated into the American Joint Committee on Cancer staging system, the National Comprehensive Cancer Network practice guidelines, and numerous national and international consensus statements., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Evaluate characteristics and risk factors for patients with advanced cutaneous squamous cell carcinoma (cSCC)., Study Design: Retrospective case series., Setting: Tertiary care center., Patients and Methods: Chart review of patients with cSCC undergoing a parotidectomy (2003-2012)., Results: Of 218 patients identified, 49% presented with a new primary lesion (n = 107) and 51% with a recurrence (n = 111). Parotid lymph nodes were positive in 52% of patients; 81% had a concurrent neck dissection, and 28% had cervical lymph node metastases. In 18% of patients, both parotid and cervical nodes were positive, while 44% were both parotid and cervical node negative; 33% had positive parotid and negative cervical nodes, and only 5% had negative parotid and positive cervical nodes. The overall 2- and 5-year survival rates were 0.71 and 0.58. Overall 5-year survival was lower for patients presenting with recurrent (0.49) versus new primary disease (0.69; P = .04). In addition, decreased overall 5-year survival rates were associated with cervical lymph node involvement (0.47 vs. 0.62; P = .01). There was no difference in overall survival when stratified by parotid lymph node involvement (P = .85), margin status (P = .67), perineural invasion (P = .42), facial nerve sacrifice (P = .92), or type of parotid operation performed (P = .51)., Conclusions: In this study, cervical, but not parotid, lymph node involvement was associated with poor outcomes in patients with advanced cSCC requiring a parotidectomy. In patients without evidence of cervical or parotid lymph node involvement, a neck dissection may be spared, given there is a 5% chance of occult disease.

Objective: Sentinel lymph node biopsy (SLNB) is standard of care for melanoma, but its role in cutaneous squamous cell carcinoma (cSCC) has not been established. Study objectives include: (1) analyze the feasibility and reliability SLNB for head and neck (H&N) cSCC and (2) identify risk factors associated with a positive SLN., Data Sources: MEDLINE, PubMed, Cochrane, and ASCO databases searches conducted (1946-2013)., Review Methods: Using the PRISM model, a comprehensive systematic review of H&N cSCC SLNB studies with associated recurrence rates was conducted. Dual-blinded data extraction identify primary outcomes (successful SLN harvest and false omission rate) and secondary outcomes (risk factors associated with a +SLN)., Results: Two hundred twenty-one articles were screened; 73 patients from 11 publications met inclusion criteria (3 case series; 8 prospective cohorts). Studies ranged from 1 to 15 patients (median 5). Median age was 74 years. Median follow-up was 21.5 months. Average tumor size was 3.09 cm. At least 1 SLN was identified in 100% of patients (median 2). Ten (13.5%) had a positive SLN; no additional metastatic nodes were identified in 9 patients receiving completion lymphadenectomy. Tumor diameter was not associated with SLN status (P = .09; 95% CI, -.27 to 3.02). Risk factors (tumor depth, perineural invasion, location, differentiation) were not consistently recorded. Three of 63 (4.76%) failed regionally following a negative SLNB., Conclusion: H&N cSCC SLNB is feasible and reliable for staging, with a false omission rate of 4.7% mirroring melanoma. Prospective studies documenting high risk features are required to further define its role.

Traumatic facial defects negatively impact speech, mastication, deglutition, dental hygiene, and psychosocial well-being. Reconstruction must address restoration of function and aesthetics to provide quality of life. This report describes soft-tissue reconstruction using a novel magnet-retained facial prosthesis without osseointegrated abutments, performed in a patient after traumatic loss of the entire left lower part of the face, including lips, commissure, and mentum. This reconstructive technique successfully addressed the cosmetic defect while also restoring function with respect to speech and oral nutrition. For this reason, magnet-retained facial prosthesis should be added to free tissue transfer and regional flaps as a reasonable option in the reconstructive algorithm for complex soft-tissue defects of the lower face.

Purpose: Conflicting locations of the spinal accessory nerve (SAN) with respect to the internal jugular vein (IJV) are reported in the literature and anatomy texts. The objective of this study is to analyze this anatomic relationship specifically at the level of the posterior belly of the digastric muscle where it is encountered most often during surgery., Material and Methods: This study is a case series with planned chart review of all operative reports for neck dissections/explorations performed between June 2002 to June 2008 at an academic tertiary care referral center. Inclusion criteria required intraoperative identification of the SAN at the level of the posterior belly of the digastric muscle. Patients undergoing revision neck dissection were excluded. Data is presented using descriptive statistics., Results: One hundred ninety-seven patients were identified; 175 met inclusion criteria. Thirty-two patients received bilateral neck dissections/explorations, resulting in a total of 207 SANs for analysis. The most common location of the SAN was lateral to the IJV (198; 95%). In 6 (2.8%) cases the SAN was identified medial to the IJV and 2 nerves pierced the IJV. A new variant of the SAN splitting around the SAN was identified., Conclusion: The majority of SANs course lateral to the IJV at the level of the posterior belly of the digastrics muscle (95%). This intraoperative finding differs from cadaveric studies. Discrepancies may reflect variation in the level at which the nerve was identified, as well as tissue changes related to cadaver versus in vivo studies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To investigate risk factors associated with papillary thyroid microcarcinoma (PTM) involving the thyroid lobes bilaterally at the time of diagnosis. In doing so, the authors hope to identify a subset of PTM patients who may benefit from more aggressive surgical intervention with a total thyroidectomy., Study Design: A prospective cohort study of all newly diagnosed, previously untreated PTM patients presenting between 1998 and 2008., Setting: Tertiary care military hospital., Subjects and Methods: Following total thyroidectomy, patients were grouped according to unilateral versus bilateral PTM thyroid lobe involvement. The primary outcome variable was PTM in both thyroid lobes. Independent variables of interest included patient demographics, tumor stage, nodule size, tumor focus size, and tumor focality. Univariate analysis was used to investigate risk factors associated with bilateral lobe PTM., Results: Five of 25 (20%) patients had bilateral thyroid lobe PTM at presentation. There was no statistically significant difference between the unilateral versus bilateral groups with respect to age, gender, history, stage, and tumor size. Bilateral thyroid lobe PTM occurred significantly more often in the setting of multifocal PTM (4/7, 57%) versus unifocal PTM (1/18 cases, 5.6%; P = .012). The odds ratio of harboring occult PTM in the contralateral lobe at time of diagnosis in the setting of multifocal PTM was 23 times greater than the unifocal counterpart (95% confidence interval, 1.9-27.9)., Conclusion: Multifocal PTM is a significant risk factor associated with bilateral thyroid lobe involvement at presentation. Surgeons are justified and encouraged to offer multifocal PTM patients completion thyroidectomy as part of their oncologic treatment.

Unknown primary carcinoma presenting as cervical lymph node metastasis accounts for approximately 5% of all head and neck malignancies. The typical presentation involves a middle-aged man with a painless neck mass that has been present for several months. Over 90% of these malignancies represent squamous cell carcinoma originating within Waldeyer's ring (lymphoid tissue of the nasopharynx, tonsil, and base of tongue). The remainder are comprised of adenocarcinoma, melanoma, and other rare histologic variants. The ability to identify the occult primary tumor is imperative because identification allows site-specific therapy and avoidance of wide-field radiation side effects. Following confirmation of metastatic cervical disease with fine-needle aspiration, all patients presenting with an unknown primary carcinoma require a thorough head and neck history and physical examination, radiographic imaging, panendoscopy with directed biopsies of Waldeyer's ring, and bilateral tonsillectomy. Positron emission tomography has proved helpful in identifying occult primary tumors of the head and neck region.

Objective: To determine (1) the reliability of sentinel lymph node (SLN) biopsy and (2) the need for cytokeratin 20 (CK-20) immunostaining in the staging of head and neck Merkel cell carcinoma (MCC)., Design: Retrospective cohort study (median follow-up of 34.5 months)., Setting: Tertiary care center., Patients: Ten patients with head and neck MCC who underwent regional staging with SLN biopsy (SLNB) and CK-20 immunostaining., Interventions: Sentinel lymph nodes were identified using preoperative lymphoscintigraphy, intraoperative gamma probe, and isosulfan blue dye. The SLNs were evaluated with hematoxylin-eosin and CK-20 immunostaining. Patients with negative SLNB results were followed up clinically., Main Outcome Measures: Percentage of positive SLNs, regional recurrence in the setting of a negative finding from SLNB, and percentage of positive SLNs requiring CK-20 immunostaining for diagnosis of micrometastatic MCC., Results: At least 1 SLN was identified in every patient. Of 24 nodes, 19 (79%) were from the neck region and 5 (21%) were from the parotid basin. Two of the 24 SLNs, in 2 (20%) of 10 patients, were positive for metastatic disease. Both positive SLNs appeared negative on hematoxylin-eosin-stained sections, but small foci of micrometastatic MCC were identified with CK-20 immunostaining. No cranial nerve complications occurred. Regional failure in the setting of a negative finding on SLNB was observed in 1 (12%) of 8 patients., Conclusions: Biopsy of SLNs represents a safe and reliable technique for regional staging of MCC of the head and neck. It provides pathologists with a limited number of SLNs for focused analysis, which is imperative because hematoxylin-eosin immunostaining is often insufficient for identifying micrometastatic MCC. The use of anti-CK-20 antibody allows accurate identification of micrometastatic MCC.

Background: The survival of patients with head and neck squamous cell carcinoma (HNSCC) remains unaffected despite recent therapeutic advances. To reverse this trend, reliable and clinically applicable markers of tumor aggressiveness must be identified. One such marker may be the tumor-associated macrophage content. The authors hypothesized that tumor-associated macrophages contribute to HNSCC aggressiveness, and the objective of the current study was to prove this hypothesis using mRNA expression analysis and a large cohort of clinical specimens., Methods: Oligonucleotide microarray analysis was performed on a prospective cohort of 20 patients with previously untreated oral cavity or oropharynx squamous cell carcinoma (OC/OP SCCA) and on normal oropharyngeal mucosa from 4 patients. After determining whether macrophage chemoattractants were produced by tumors, conditioned media from three HNSCC cell lines were used to quantify macrophage migration in an in vitro assay. A high-density tissue microarray of 102 patients with previously untreated OC/OP SCCA was stained immunohistochemically for CD68 to identify tissue macrophages, and the results were correlated with clinicopathologic data and survival., Results: Monocyte chemoattractant protein 1 was up-regulated significantly in tumors compared with normal mucosa (P=0.0025; fold change=1.89). All University of Michigan SCC tumor cell line conditioned media caused a significant increase in macrophage migration (P <0.05). Tissue microarray data revealed that macrophage content of the primary tumor was associated strongly with lymph node metastasis (P <0.0001), extracapsular lymph node spread (P=0.0001), and advanced clinical disease stage (P=0.0002). When it was evaluated along with other clinicopathologic data, the macrophage content was found to be an independent predictor of lymph node metastasis (P <0.0001)., Conclusions: Primary tumor macrophage content is a strong predictor of tumor aggressiveness in HNSCC.

Objective: To investigate differences in gene expression profiles between oral cavity/oropharynx squamous cell carcinoma (OC/OP SCC) primary tumors that have metastasized to cervical lymph nodes and nonmetastatic OC/OP SCC tumors., Design: Oligonucleotide microarray analysis of primary tumors was used to produce gene expression profiles. Profile comparisons between metastatic and nonmetastatic tumors were performed using principal component analysis, t test, and fold change differences. A similar comparison between metastatic tumors and noncancer oral mucosa samples was performed to ensure tumor origin., Subjects: A prospective cohort of 20 patients with previously untreated OC/OP SCC who underwent pathologic staging following surgical resection and lymphadenectomy., Results: Of the approximately 9600 genes profiled, 101 demonstrated significant expression differences between the metastatic and nonmetastatic tumors (fold change > or =1.5; P<.01). Among this subset, 57 genes also exhibited significant differences between metastatic tumors and normal mucosa samples (fold change > or =1.5; P<.05). This profile included genes related to the extracellular matrix, adhesion, motility, inflammation, and protease inhibition. Collagen type 11 alpha-1 (COL11A1) demonstrated the greatest differential expression between metastatic and nonmetastatic OC/OP SCC tumors (fold change=7.61; P=.002). Tissue inhibitor of metalloproteinase 1 (TIMP-1) also demonstrated increased expression in metastatic tumors (fold change=3.3; P=.003)., Conclusions: Metastatic OC/OP SCC has a distinct gene expression profile compared with nonmetastatic OC/OP SCC and normal oral mucosa. This metastatic profile includes genes related to the extracellular matrix, adhesion, motility, and protease inhibition. Knowledge gained through tumor gene expression profiling may facilitate early detection of aggressive tumors and targeted therapeutic interventions.

We implemented a protein microarray approach to identify proteins that induce a humoral response in colon cancer. Solubilized proteins from the LoVo colon adenocarcinoma cell line were separated into 1760 fractions, arrayed onto nitrocellulose-coated slides, and hybridized with individual sera from 15 newly diagnosed patients with colon cancer, 15 with lung cancer, and 15 healthy subjects. 39/1760 fractions showed enhanced reactivity with sera from patients with colon cancer (p < 0.01) relative to healthy controls. A distinct pattern of reactivity was observed with sera from colon cancer relative to lung cancer. One fraction that exhibited reactivity with 9/15 colon cancer sera was subjected to mass spectrometry leading to the identification of ubiquitin C-terminal hydrolase isozyme 3 (UCH-L3) as a constituent. To validate the occurrence of autoantibodies to UCH-L3, independent analysis was done by means of Western blots. UCH-L3 antibodies were detected in 19/43 sera from patients with colon cancer, and in 0/54 sera from subjects with lung cancer (24), colon adenoma (15) or otherwise healthy (15). Our findings indicate the occurrence of an immune response to a broad set of antigens in colon cancer and the feasibility of identifying the antigenic targets using a combination of protein microarrays and mass spectrometry.

Objectives: To determine (1) the reliability of sentinel lymph node mapping with biopsy (SLNB) in head and neck cutaneous melanoma to accurately stage nodal basins and (2) the safety of SLNB in both the neck and parotid regions., Design: Retrospective cohort study with a median follow-up of 25 months. All patients had a minimum follow-up of 1 year., Setting: Academic medical center., Patients: Eighty evaluable patients diagnosed as having head and neck cutaneous melanoma and staged using SLNB., Interventions: Sentinel lymph nodes were identified using preoperative lymphoscintigraphy and a combination of intraoperative gamma probe and isosulfan blue dye. Patients with a SLN positive for melanoma underwent therapeutic lymphadenectomy followed by an evaluation for adjuvant therapies. Patients with a negative SLNB result were followed up clinically., Main Outcome Measures: Percentage of positive SLNs, regional recurrence in the setting of a negative SLNB result (false-negative rate), and procedure complications., Results: The mean Breslow depth was 2.35 mm. A SLN was identified in 77 (96.3%) of cases, with an average of 2.18 nodes per patient. Of the sentinel nodes identified, 74% were from the neck region. The remaining 26% were from the parotid basin. No facial nerve complications occurred. Of the patients, 14 (18%) were SLN positive for metastatic melanoma. The regional failure rate in the setting of a negative SLNB result was 4.5%., Conclusions: Sentinel lymph node mapping with biopsy is a reliable technique to diagnose regional spread from head and neck cutaneous melanoma. This procedure can be performed in both neck and parotid nodal basins with safety and accuracy similar to non-head and neck sites.