Proposal for standardized ultrasound analysis of the salivary glands: Part 1 submandibular gland.

Objectives: The Salivary Gland Committee of the American Academy of Otolaryngology-Head and Neck Surgery seeks to standardize terminology and technique for ultrasonograpy used in the evaluation and treatment of salivary gland disorders. Methods: Development of expert opinion obtained through interaction with international practitioners representing multiple specialties. This committee work includes a comprehensive literature review with presentation of case examples to propose a standardized protocol for the language used in ultrasound salivary gland assessment. Results: A multiple segment proposal is initiated with this focus on the submandibular gland. We provide a concise rationale for recommended descriptive language highlighted by a more extensive supplement that includes an extensive literature review with additional case examples. Conclusion: Recommendations are provided to improve consistency both in performing and reporting submandibular gland ultrasound.

Effect of preoperative programmed death-1 or programmed death ligand-1 immune check point inhibition on complications after surgery for primary head and neck cancer.

BACKGROUND: There is sparse literature on the effect of preoperative immunotherapy on complications after surgery for primary head and neck squamous cell carcinoma (HNSCC). The objectives are to compare complication rates in patients receiving surgery with and without neoadjuvant immune checkpoint inhibitors (nICI) for primary HNSCC and to evaluate factors associated with increased odds of surgical complications. METHODS: A retrospective review of patients who underwent ablation and free flap reconstruction or transoral robotic surgery (TORS) for primary HNSCC between 2017-2021 was conducted. Complications were compared between patients who underwent surgery with or without nICI before and after propensity score matching. Regression analysis to estimate odds ratios was performed. RESULTS: A total of 463 patients met inclusion criteria. Free flap reconstruction constituted 28.9% of patients and TORS constituted 71.1% of patients. nICI was administered in 83 of 463 (17.9%) patients. There was no statistically significant difference in surgical, medical, or overall complications between patients receiving surgery with or without nICI. In the unmatched cohort, multivariable model identified non-White race, former/current smoking history, free flap surgery, and perineural invasion as factors significantly associated with increased complications. In the matched cohort, multivariable model identified advanced age and free flap surgery as factors significantly associated with increased complications. PLAIN LANGUAGE SUMMARY: It is safe to give immunotherapy before major surgery in patients who have head and neck cancer. Advanced age, non-White race, current/former smoking, free flap surgery, and perineural invasion may be associated with increased the odds of surgical complications.

Sentinel lymph node biopsy for head and neck malignancies utilizing simultaneous radioisotope gamma probe and indocyanine green fluorescence navigation.

We depict an innovative surgical approach for sentinel lymph node biopsy (SLNB) in head and neck malignancies that utilizes both near-infrared (NIR) imaging with indocyanine green (ICG) dye and hand-held gamma probe intraoperatively to isolate and excise SLNs. Twenty-one patients presented to our institution with cutaneous melanoma, cutaneous squamous cell carcinoma (SCC), and oral cavity SCC tumors that met criteria for SLNB based on tumor depth and histology. The video offers a step-by-step approach for this technique along with descriptions of recommended equipment. Among 21 patients, two patients had positive SLNs on final pathology. One patient developed a local recurrence over an average of 16.2 months of follow-up (SD = 15.6). SLNB with ICG and radionucleotide co-localization may enhance the identification of sentinel nodes without compromising outcomes in the hands of surgeons well-versed in the technique.

Perioperative opioids and survival outcomes in resectable head and neck cancer: A systematic review.

BACKGROUND: Opioids are a mainstay in pain control for oncologic surgery. The objective of this systematic review is to evaluate the associations of perioperative opioid use with overall survival (OS) and disease-free survival (DFS) in patients with resectable head and neck cancer (HNC). METHODS: A systematic review of PubMed, SCOPUS, and CINAHL between 2000 and 2022 was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies investigating perioperative opioid use for patients with HNC undergoing surgical resection and its association with OS and DFS were included. RESULTS: Three thousand three hundred seventy-eight studies met initial inclusion criteria, and three studies representing 562 patients (intraoperative opioids, n = 463; postoperative opioids, n = 99) met final exclusion criteria. One study identified that high intraoperative opioid requirement in oral cancer surgery was associated with decreased OS (HR = 1.77, 95% CI 0.995-3.149) but was not an independent predictor of decreased DFS. Another study found that increased intraoperative opioid requirements in treating laryngeal cancer was demonstrated to have a weak but statistically significant inverse relationship with DFS (HR = 1.001, p = 0.02) and OS (HR = 1.001, p = 0.02). The last study identified that patients with chronic opioid after resection of oral cavity cancer had decreased DFS (HR = 2.7, 95% CI 1.1-6.6) compared to those who were not chronically using opioids postoperatively. CONCLUSION: An association may exist between perioperative opioid use and OS and DFS in patients with resectable HNC. Additional investigation is required to further delineate this relationship and promote appropriate stewardship of opioid use with adjunctive nonopioid analgesic regimens.

Margins in Stage I and II Oral Cavity Squamous Cell Carcinoma: A Review From the American Head and Neck Society.

Importance: The assessment and management of surgical margins in stage I and II oral cavity squamous cell carcinoma is one of the most important perioperative aspects of oncologic care, with profound implications for patient outcomes and adjuvant therapy. Understanding and critically reviewing the existing data surrounding margins in this context is necessary to rigorously care for this challenging group of patients and minimize patient morbidity and mortality. Observations: This review discusses the data related to the definitions related to surgical margins, methods for assessment, specimen vs tumor bed margin evaluation, and re-resection of positive margins. The observations presented emphasize notable controversy within the field about margin assessment, with early data coalescing around several key aspects of management, although studies are limited by their design. Conclusions and Relevance: Stage I and II oral cavity cancer requires surgical resection with negative margins to obtain optimal oncologic outcomes, but controversy persists over margin assessment. Future studies with improved, well-controlled study designs are required to more definitively guide margin assessment and management.

Integrative Metatranscriptomic Analysis Reveals Disease-specific Microbiome-host Interactions in Oral Squamous Cell Carcinoma.

Studies on the microbiome of oral squamous cell carcinoma (OSCC) have been limited to 16S rRNA gene sequencing. Here, laser microdissection coupled with brute-force, deep metatranscriptome sequencing was employed to simultaneously characterize the microbiome and host transcriptomes and predict their interaction in OSCC. The analysis involved 20 HPV16/18-negative OSCC tumor/adjacent normal tissue pairs (TT and ANT) along with deep tongue scrapings from 20 matched healthy controls (HC). Standard bioinformatic tools coupled with in-house algorithms were used to map, analyze, and integrate microbial and host data. Host transcriptome analysis identified enrichment of known cancer-related gene sets, not only in TT versus ANT and HC, but also in the ANT versus HC contrast, consistent with field cancerization. Microbial analysis identified a low abundance yet transcriptionally active, unique multi-kingdom microbiome in OSCC tissues predominated by bacteria and bacteriophages. HC showed a different taxonomic profile yet shared major microbial enzyme classes and pathways with TT/ANT, consistent with functional redundancy. Key taxa enriched in TT/ANT compared with HC were Cutibacterium acnes, Malassezia restricta, Human Herpes Virus 6B, and bacteriophage Yuavirus. Functionally, hyaluronate lyase was overexpressed by C. acnes in TT/ANT. Microbiome-host data integration revealed that OSCC-enriched taxa were associated with upregulation of proliferation-related pathways. In a preliminary in vitro validation experiment, infection of SCC25 oral cancer cells with C. acnes resulted in upregulation of MYC expression. The study provides a new insight into potential mechanisms by which the microbiome can contribute to oral carcinogenesis, which can be validated in future experimental studies. Significance: Studies have shown that a distinct microbiome is associated with OSCC, but how the microbiome functions within the tumor interacts with the host cells remains unclear. By simultaneously characterizing the microbial and host transcriptomes in OSCC and control tissues, the study provides novel insights into microbiome-host interactions in OSCC which can be validated in future mechanistic studies.

Variance in 3D anatomic localization of surgical margins based on conventional margin labeling in head and neck squamous cell carcinoma.

OBJECTIVE: In head and neck cancer (HNC), positive margins are strongly predictive of treatment failure. We sought to measure the accuracy of localization of margin sampling sites based on conventional anatomic labels using a digital 3D-model. METHODS: Preoperative CT scans for 9 patients with HNC treated operatively at our institution were imported into a multiplanar radiology software, which was used to render a digital 3D model of each tumor intended to represent the resection specimen. Surgical margin labels recorded during the operative case were collected from pathology records. Margin labels (N = 64) were presented to participating physicians.Participants were asked to mark the anatomic location of each surgical margin using the 3D-model and corresponding radiographic planes for reference.For each individual margin, the 3D coordinates of each participant's marker were used to calculate a mean localization point called the geometric centroid. Mean distance from individual markers to the centroid was compared between participantsand margin types. RESULTS: Amongst 7 surgeons, markers were placed a mean distance of 12.6 mm ([SD] = 7.5) from the centroid.Deep margins were marked with a greater mean distance than mucosal/skin margins (19.6 [24.8] mm vs. 15.3 [14.9] mm, p = 0.034). When asked to relocate a margin following re-resection, surgeons marked a point an average of 20.6 [12.4] mm from their first marker with a range of 3.9- 45.1 mm. CONCLUSIONS: Retrospective localization of conventionally labeled margins is an imprecise process with variability across the care team. Future interventions targeting margin documentation and communication may improve sampling precision.

Feasibility and Cost of Telehealth Head and Neck Cancer Survivorship Care: A Systematic Review.

OBJECTIVE: Evaluate the feasibility and cost-effectiveness of telehealth head and neck cancer (HNC) survivorship care. DATA SOURCES: Ovid MEDLINE, Embase, Scopus, CINAHL. REVIEW METHODS: A systematic search for peer-reviewed feasibility studies on telehealth models for HNC survivorship care published between 2005 and 2021 was conducted using the terms "head and neck cancer" and "telehealth" and their synonyms. Inclusion criteria were studies on telehealth survivorship program interventions for HNC patients with quantitative feasibility outcome measures (eg, enrollment, retention, attrition/dropout rate, adherence/task completion rate, patient satisfaction, cost). RESULTS: Thirty-eight studies out of 1557 identified met inclusion criteria and were included for analysis. Feasibility outcomes evaluated were enrollment and attrition rates, adherence/task completion rates, patient satisfaction, and user feedback surveys in different survivorship domains. Patient enrollment ranged from 20.8% to 85.7%, while attrition ranged from 7% to 47.7%. Overall, adherence was 30.2% higher in the intervention group than in the control group (46.8% vs 16.6%). Studies with cost analysis found telehealth models of care to be statistically significantly less expensive and more cost-efficient than the standard model of care, with a $642.30 saving per patient (n = 3). Telehealth models also substantially reduced work time saving per visit (on average, 7 days per visit). CONCLUSION: While telehealth survivorship programs are feasible and cost-effective and are associated with improved patient outcomes, they might not be ideal for every patient. Further investigations are needed to understand the role of telehealth in survivorship care, given the variability in study design, reporting, measures, and methodological quality.

Minimally invasive retroauricular approach parotidectomy: A pictorial essay.

The surgical approach to a parotid neoplasm has traditionally been taught through a modified-Blair incision. This approach results in a visible scar in the preauricular, retromandibular, and upper neck skin. Various modifications have been undertaken which aim to improve cosmesis either by decreasing overall incision length and/or relocation of the incision to the hairline via what is commonly described as a "facelift approach". We describe a novel minimally invasive parotidectomy approach which utilizes a single retroauricular incision. This approach eliminates both the preauricular scar as well as the extended incision in the hairline and additional skin flap elevation which accompanies it. Sixteen patients underwent parotidectomy using this minimally invasive incision and the excellent clinical outcomes are reviewed. The minimally invasive retroauricular approach to parotidectomy provides excellent exposure with no visible incision/scar in appropriately selected patients.

Examination of care processes and treatment optimization for head and neck cancer patients in a community setting "hub and hub" model.

Objective: To examine referral pattern, the timing of diagnostic/staging processes, and treatment initiation for new head and neck cancer patients in a community setting. Methods: Patients with a newly diagnosed previously untreated diagnosis of head neck cancer managed at Asplundh Cancer Pavilion/Abington Memorial Hospital from October 2018 to March 2020. Source of referral and preceding workup were examined as well as intervals between initial head and neck consult and various timepoints of treatment initiation. Results: One hundred and five patients were included in the study. The primary referral sources were external general otolaryngology (56.3%). Oral surgery and dermatology obtained tissue biopsy approximately 80% of the time before referral. The average time from the ordering of initial staging positron emission tomography/computed tomography to finalized results was 14 days (range: 10-25 days). Patients referred from dermatology and oral surgery were more likely to require single modality care, namely definitive surgical management. Time to treatment initiation average was 37 days (range: 29-41 days). Patients with longer treatment times noted significantly higher times to both radiation and medical oncology consults (48.42 vs. 18.13 days; P < 0.001). Conclusions: No notable differences in treatment initiation times were identified based on referral source or extent of workup performed before head/neck surgery consult. It appears the largest opportunities for improvement in terms of reducing overall treatment length exist in the optimization of radiation initiation time.

Evaluating the impact of smoking on disease-specific survival outcomes in patients with human papillomavirus-associated oropharyngeal cancer treated with transoral robotic surgery.

BACKGROUND: When treated nonsurgically with definitive chemoradiation, smokers with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a worse prognosis compared with their nonsmoking counterparts. To the authors' knowledge, the prognostic significance of smoking in surgically treated patients is unknown. METHODS: The current study is a retrospective case series of patients with HPV-positive OPSCC who underwent upfront transoral robotic surgery at a single institution from 2010 through 2017. Exclusion criteria were nonoropharyngeal primary tumors, histology other than SCC, HPV-negative tumors, previous history of head and neck cancer, and/or previous head and neck radiotherapy. Recurrence-free survival (RFS), overall survival, and disease-specific survival were compared using the Kaplan-Meier method and the log-rank test. Smoking history was categorized as never smokers (<1 pack-year), current smokers (smoking at the time of the cancer diagnosis), and former smokers. RESULTS: A total of 258 patients met the study criteria. The average age was 60 years, and approximately 87% of patients were male. A total of 148 patients (57.4%) were smokers whereas 110 (42.6%) reported never smoking. There were 44 active smokers (17.1%) and 104 former smokers (40.3%). The median follow-up was 3.23 years. There were 17 patients of disease recurrence. Smoking pack-year history was not found to be significant for RFS (hazard ratio, 1.01; 95% CI, 0.99-1.03 [P = .45]). There was no significant difference in RFS noted between never and ever smokers (92% vs 89.8%; P = .85) nor was there a difference observed between never, former, and current smokers (92% vs 91.5% vs 86.1%, respectively; P = .69). CONCLUSIONS: A smoking history is common in patients with HPV-positive OPSCC. In the current study, HPV-positive smokers were found to have excellent survival and locoregional control, similar to their nonsmoking counterparts. The results of the current study do not support the exclusion of smokers with early-stage, HPV-positive OPSCC from transoral robotic surgery-based deintensification trials.

Investigation of the Longevity of the Endoscopic Midface Lift.

IMPORTANCE: To our knowledge, until now, the efficacy and durability of the transtemporal endoscopic preperiosteal midface lift has not been reported in the literature. OBJECTIVE: To determine the efficacy and longevity of the endoscopic preperiosteal midface lift using objective measurements and validated aesthetic scales. DESIGN, SETTING, AND PARTICIPANTS: This retrospective review included patients 18 years or older who were treated for aging midface by endoscopic midface lift by the senior author (A.E.W.) between June 2000 and August 2016. Patients were categorized based on length of follow-up into 3 groups: (1) short-term (1-3 years), (2) intermediate-term (3-5 years), and (3) long-term (>5 years). INTERVENTIONS OR EXPOSURES: Endoscopic preperiosteal midface lift. MAIN OUTCOMES AND MEASURES: (1) Objective measurements of midfacial height (the width of the interzygomatic distance of the midface to the medial canthus [WIZDOM-MC]), (2) validated regional aesthetic scales, and (3) global aesthetic scoring systems measured preoperatively, 3 to 6 months postoperatively, and at the most recent follow-up visit. RESULTS: Adult patients 18 years or older (median [range] age, 59 [31-79] years) who were treated for aging midface by undergoing an endoscopic midface lift were included in this study. The medical records of 143 patients were reviewed (135 women and 8 men). The endoscopic midface lift resulted in objective improvement in midfacial height. The median WIZDOM-MC decreased by 3.4 mm after the endoscopic midface lift (interquartile range [IQR], 2.3-4.4 mm; P < .001), thus shortening the elongated lower eyelid. At 5 to 15 years after surgery, there was a sustained decrease in median WIZDOM-MC of 2.1 mm (IQR, 0.8-3.1 mm; P < .001). Improvement in the infraorbital hollow was also sustained in patients at more than 5 years' follow-up (IQR, 0-1.0; P < .001). Improvements in upper cheek fullness and lower cheek fullness were maintained at 3 to 5 years and tended to be at baseline at more than 5 years. Global aesthetic improvement scores remained significantly improved at 5 to 15 years' follow-up. CONCLUSIONS AND RELEVANCE: There is a significant, objective improvement in midfacial height after the endoscopic midface lift that persists for up to 15 years. Validated midfacial scales and global aesthetic scoring systems demonstrate sustained improvement in midface appearance over time. Surgery that minimally disrupts the zygomatic and orbicularis retaining ligaments can provide long-lasting aesthetic improvements. LEVEL OF EVIDENCE: 4.

Clinical Value of Tc99m-MIBI SPECT/CT Versus 4D-CT or US in Management of Patients With Hyperparathyroidism.

Localization of parathyroid adenomas for treatment of primary hyperparathyroidism can be challenging. This retrospective study compared single-photon emission computed tomography/computed tomography (SPECT/CT), 4D-CT, and US studies in detection of adenomas prior to surgery. A retrospective chart review was performed on all consecutive patients with parathyroid adenoma presenting to an urban tertiary care medical center. A total of 58 patients (45 female, 13 male) underwent surgery for parathyroid adenoma. Patients aged 28 to 80 years (mean: 58.8) with parathyroid hormone levels ranging from 42 to 424 pg/mL (mean: 168). All patients underwent preoperative SPECT/CT with 20 mCi technetium-99m MIBI (99mTc-MIBI). Fifty-three patients had additional US imaging and 14 patients had 4D-CT scans. Additionally, 34 patients had injection of 20 mCi 99mTc-MIBI on the day of surgery. Pathological correlation was performed. Comparing SPECT/CT versus 4D-CT resulted in sensitivity (77% vs 80%), specificity (71% vs 75%), and accuracy (77% vs 79%). Ultrasound was less sensitive with similar specificity (44%, 86%, respectively). Combination of SPECT/CT and 4D-CT increased sensitivity to 88%, specificity to 100%, and accuracy to 89%. Combining SPECT/CT with US resulted in sensitivity of 85%, specificity of 83%, and accuracy of 85%. Intraoperative localization substantially improved in patients who received preoperative injections. The SPECT/CT remains the best imaging modality for preoperative localization of parathyroid adenomas with high sensitivity. Combining SPECT/CT with US resulted in increased sensitivity and accuracy. For suspicion of ectopic cases or suspicion of unidentifiable adenoma with negative scintigraphy, addition of 4D-CT is recommended. Intraoperative localization and adjunctive imaging may improve surgical management of patients with hyperparathyroidism.

Patterns of distant metastasis in head and neck cancer at presentation: Implications for initial evaluation.

IMPORTANCE: Evaluation of distant metastasis (DM) is part of every new cancer evaluation. Understanding DM presentation patterns may impact the imaging workup of Head and Neck Squamous Cell Carcinoma (HNSCC). OBJECTIVE: Examine the frequency and location of DM at presentation in HNSCC. We hypothesize that DM are rare, and the lung is the most common site for DM. Secondary evaluation includes identifying patient and tumor factors predictive of DM, and the implications for selection of workup imaging. DESIGN: Data from the National Cancer Data Base (NCDB) from 2010 to 2015 were analyzed. Subsites evaluated included oral cavity, oropharynx, larynx, hypopharynx, and nasopharynx. Sites of distant metastasis were evaluated in available cases and analyzed. SETTING: Population based database study. RESULTS: 151,730 cases were available for analysis. Nasopharynx had the highest percentage of M1 disease (9.1%) followed by hypopharynx (7.3%). Excluding the nasopharynx (NP), 3.1% of cases were reported as M1. Advanced T-stage, positive N-stage, and N3 status were all predictors of M1 status on univariate and multivariate analysis for all subsites (P < 0.05). Where site of metastasis was available, most (53.1%) DM cases presented with at least lung involvement. In nasopharynx cancers, only 32.8% of DM included the lung. CONCLUSIONS AND RELEVANCE: Distant metastasis in HNSCC are rare events. PET/CT offers many advantages, but for routine distant metastasis evaluation in HNSCC, CT scan of the chest may be more cost-effective.

Moving Toward a Systematic Approach for Reporting Salivary Gland Cytopathology: An Institutional Experience and Literature Review.

CONTEXT.­: Despite the clinical utility of fine-needle aspiration for the diagnosis of salivary pathologies, salivary lesions remain one of the most challenging areas in cytopathology. This is partially because there is no consensus on how to report salivary gland cytopathology, which has resulted in inconsistent terminology among institutions and individual cytopathologists and in confusion in communication among cytopathologists and ordering providers. OBJECTIVE.­: To summarize our experience with an institutional salivary gland cytopathology reporting system, as an initiative to promote collaborative work toward a consensus on a reporting system. DESIGN.­: We developed an empirical 6-tier classification reporting system. Slides of 107 salivary gland fine-needle aspirations with subsequent histology slides were reviewed and reclassified using the 6-tier system. The performance of the cytology reporting system was evaluated with the histology diagnoses serving as the gold standard. RESULTS.­: Fine-needle aspiration diagnoses made based on the institutional 6-tier classification system were generally consistent with histology diagnoses for the disease spectrum reported in this study. The sensitivity, specificity, positive predictive value, and negative predictive value for diagnosing malignancies with the system were 86% (12 of 14), 93% (40 of 43), 80% (12 of 15), and 95% (40 of 42), respectively. The risk of malignancy increased from 0% (0 of 13) for negative for neoplasm to 7% (2 of 29) for benign neoplasm, 67% (2 of 3) for suspicious for malignancy, and 83% (10 of 12) for positive for malignancy. CONCLUSIONS.­: The institutional 6-tier system provides a succinct, risk-of-malignancy-based system to report salivary gland cytology. Our experience with this system helps to pave the way for the adoption of the Milan System for Reporting Salivary Gland Cytopathology.

International neuromonitoring study group guidelines 2018: Part II: Optimal recurrent laryngeal nerve management for invasive thyroid cancer-incorporation of surgical, laryngeal, and neural electrophysiologic data.

The purpose of this publication was to inform surgeons as to the modern state-of-the-art evidence-based guidelines for management of the recurrent laryngeal nerve invaded by malignancy through blending the domains of 1) surgical intraoperative information, 2) preoperative glottic function, and 3) intraoperative real-time electrophysiologic information. These guidelines generated by the International Neural Monitoring Study Group (INMSG) are envisioned to assist the clinical decision-making process involved in recurrent laryngeal nerve management during thyroid surgery by incorporating the important information domains of not only gross surgical findings but also intraoperative recurrent laryngeal nerve functional status and preoperative laryngoscopy findings. These guidelines are presented mainly through algorithmic workflow diagrams for convenience and the ease of application. These guidelines are published in conjunction with the INMSG Guidelines Part I: Staging Bilateral Thyroid Surgery With Monitoring Loss of Signal. Level of Evidence: 5 Laryngoscope, 128:S18-S27, 2018.

Surgical management of the recurrent laryngeal nerve in thyroidectomy: American Head and Neck Society Consensus Statement.

"I have noticed in operations of this kind, which I have seen performed by others upon the living, and in a number of excisions, which I have myself performed on the dead body, that most of the difficulty in the separation of the tumor has occurred in the region of these ligaments…. This difficulty, I believe, to be a very frequent source of that accident, which so commonly occurs in removal of goiter, I mean division of the recurrent laryngeal nerve." Sir James Berry (1887).

Fusion proteins in head and neck neoplasms: Clinical implications, genetics, and future directions for targeting.

Fusion proteins resulting from chromosomal rearrangements are known to drive the pathogenesis of a variety of hematological and solid neoplasms such as chronic myeloid leukemia and non-small-cell lung cancer. Efforts to elucidate the role they play in these malignancies have led to important diagnostic and therapeutic triumphs, including the famous development of the tyrosine kinase inhibitor dasatinib targeting the BCR-ABL fusion. Until recently, there has been a paucity of research investigating fusion proteins harbored by head and neck neoplasms. The discovery and characterization of novel fusion proteins in neoplasms originating from the thyroid, nasopharynx, salivary glands, and midline head and neck structures offer substantial contributions to our understanding of the pathogenesis and biological behavior of these neoplasms, while raising new therapeutic and diagnostic opportunities. Further characterization of these fusion proteins promises to facilitate advances on par with those already achieved with regard to hematologic malignancies in the precise, molecularly guided diagnosis and treatment of head and neck neoplasms. The following is a subsite specific review of the clinical implications of fusion proteins in head and neck neoplasms and the future potential for diagnostic targeting.