Diagnostic Accuracy of Circulating Tumor HPV DNA Testing in Patients With a Lateral Neck Mass.

Importance: The most frequent presenting symptom for patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a lateral neck mass. Circulating tumor tissue-modified viral (TTMV)-HPV DNA is a unique biomarker produced by the fragmentation of HPV DNA during the degradation of HPV-associated tumors, and its detection and quantitation are currently being used as an adjunct to imaging in monitoring for disease recurrence and may have utility for diagnosis. Objective: To measure the diagnostic characteristics of TTMV-HPV DNA compared with gold standard tissue biopsy for diagnosing HPV-OPSCC in patients presenting with an indeterminate lateral neck mass. Design, Setting, and Participants: This prospective diagnostic test study enrolled patients 18 years or older who presented with a lateral neck mass to a large urban tertiary health care system from December 2021 to June 2023. Participants underwent standard-of-care testing to obtain a tissue diagnosis and a single TTMV-HPV DNA measurement. Main Outcomes and Measures: The primary outcome of interest was sensitivity, while specificity, positive predictive value, and negative predictive value were secondary end points. A subset analysis was performed comparing test performance metrics between TTMV-HPV DNA testing and fine-needle aspiration. Results: A total of 138 patients were included, of whom 80 (58.0%) were men, with median age of 57.5 years (IQR, 43.3-67.0 years). Of 138 patients, 87 (63.0%) had neck masses in level 2 and 47 (34.1%) had HPV-OPSCC. TTMV-HPV DNA testing exhibited a sensitivity of 95.7% (95% CI, 85.5%-99.5% [45 of 47 patients]), specificity of 97.8% (95% CI, 92.3%-99.7% [89 of 91 patients]), positive predictive value of 95.7% (95% CI, 85.5%-99.5% [45 of 47 patients]), and negative predictive value of 97.8% (95% CI, 92.3%-99.7% [89 of 91 patients]). Conclusions and Relevance: In this diagnostic study of patients presenting with a lateral neck mass, circulating TTMV-HPV DNA demonstrated excellent diagnostic test characteristics for the detection of HPV-OPSCC. Such testing may have particular utility for patients in whom obtaining adequate tissue is problematic, as is often the case with cystic neck masses and unknown primary tumors.

Utility of TTMV-HPV DNA in resolving indeterminate findings during oropharyngeal cancer surveillance.

OBJECTIVES: Clinical and imaging examinations frequently have indeterminate results during cancer surveillance, which can lead to overtreatment and cause psychological and financial harm to the patient. This study addresses the critical need to enhance diagnostic precision and decision-making in the management of HPV-associated oropharyngeal cancer. This study evaluated the utility of tumor tissue-modified viral (TTMV)-HPV DNA to resolve indeterminate disease status following definitive treatment for HPV-associated oropharyngeal cancer. MATERIALS AND METHODS: In this retrospective cohort, patients treated for HPV-associated oropharyngeal cancer at eight U.S. institutions and who received one or more TTMV-HPV DNA tests during post-treatment surveillance between February 2020 and January 2022 were included. RESULTS: Among 543 patients, 210 patients (38.7%; 210/543) experienced one or more clinically indeterminate findings (CIFs) during surveillance, with 503 CIFs recorded. Of those patients with an "indeterminate" disease status at a point during surveillance, 79 were associated with contemporaneous TTMV-HPV DNA testing. TTMV-HPV DNA testing demonstrated high accuracy (97.5%; 77/79) in correctly determining recurrence status. Patients whose disease status was "indeterminate" at the time of a positive TTMV-HPV DNA test were clinically confirmed to recur faster than those whose disease status was "no evidence of disease." Only 3% of patients (17/543) experienced indeterminate TTMV-HPV DNA tests during surveillance. Discordance between TTMV-HPV DNA tests and clinical results was minimal, with only 0.6% (3/543) of patients showing positive tests without recurrence. CONCLUSION: Our findings support the utility of circulating TTMV-HPV DNA in resolving indeterminate disease status and informing the subsequent clinical course.

The impact of distance to facility on treatment modality, short-term outcomes, and survival of patients with HPV-positive oropharyngeal squamous cell carcinoma.

PURPOSE: This study compared treatment and outcomes for patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) based on their travel distance to treatment facility. MATERIALS AND METHODS: Patients with cT1-4, N0-3, M0 HPV-positive OPSCC in the National Cancer Database from 2010 to 2019 were identified and split into four quartiles based on distance to facility, with quartile 4 representing patients with furthest travel distances. Multivariable-adjusted logistic regression and Cox proportional hazards modeling were used to analyze the primary outcome of treatment received, and secondary outcomes of clinical stage, overall survival, surgical approach (i.e., TORS versus other), and 30-day surgical readmissions. RESULTS: 17,207 patients with HPV-positive OPSCC were evenly distributed into four quartiles. Compared to patients in quartile 1, patients in quartile 4 were 40 % less likely to receive radiation versus surgery (OR = 0.60; 95 % CI = 0.54-0.66). Among the patients who received surgery, quartile 4 had a higher odds of receiving TORS treatment compared to quartile 1 (4v1: OR = 2.38; 95 % CI = 2.05-2.77), quartile 2 (4v2: OR = 2.31, 95 % CI = 2.00-2.66), and quartile 3 (4v3: OR = 1.75; 95 % CI = 1.54-1.99). Quartile 4 had a decreased odds of mortality compared to Quartile 1 (4v1: OR = 0.87; 95 % CI = 0.79-0.97). There were no differences among the quartiles in presenting stage and 30-day readmissions. CONCLUSIONS: This study found that patients with furthest travel distance to facility were more often treated surgically over non-surgical management, with TORS over open surgery, and had better overall survival. These findings highlight potential disparities in access to care for patients with HPV-positive OPSCC.

Assessing Postoperative Phosphate and Calcium/Phosphate Ratio as Surrogates for Parathyroid Hormone Following Total Thyroidectomy.

OBJECTIVE: Evaluate utility of postoperative phosphate and calcium/phosphate ratio (Ca/P) as surrogates for parathyroid hormone (PTH) following total thyroidectomy. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care hospital. METHODS: We retrospectively reviewed patients 18 years or older who underwent total thyroidectomy in a tertiary care hospital by a single surgeon from 2015 through 2021. Patients with incomplete data, pre-existing hypoparathyroidism, vitamin D deficiency, or renal failure were excluded. All patients had PTH drawn within 4 hours of surgery and serum calcium, albumin, and phosphate levels on postoperative Day 1. Corrected calcium was used to calculate a Ca/P. Receiver operating characteristic (ROC) curves were generated to compare phosphate level or Ca/P with PTH. Each possible surrogate was assessed relative to PTH cutoffs of less than 5, 10, 15, and 20 pg/mL. A good screening test was defined as having an area under the curve (AUC) greater than 0.8. RESULTS: A total of 185 patients underwent total thyroidectomy with 1 fellowship-trained otolaryngologist. Most patients were female (62%), median age 48 years. Most surgeries were performed for cancer (68%). Six (3.2%) patients required IV calcium supplementation and 2 (1.1%) required readmission for symptomatic hypocalcemia. ROC curves comparing phosphate and Ca/P to PTH at the listed cutoffs demonstrated AUC ranging from 0.55 to 0.66 and 0.61 to 0.79, respectively. None met the threshold for a good screening test. CONCLUSION: Postoperative phosphate and Ca/P ratio are not surrogates for PTH levels following total thyroidectomy. More research is needed to identify cost-effective strategies for postoperative calcium monitoring in patients undergoing total thyroidectomy. LEVEL OF EVIDENCE: Retrospective cohort study.

Evaluating human papillomavirus testing, prevalence, and association with prognosis in head and neck squamous cell carcinoma by subsite: A national cancer database study.

PURPOSE: To compare human papillomavirus (HPV) testing, prevalence, and association with prognosis between head and neck squamous cell carcinoma (HNSCC) subsites. MATERIALS AND METHODS: This study utilized the National Cancer Database (NCDB) to identify patients diagnosed with HNSCC between 2010 and 2017. Rates of HPV testing, HPV-positivity, and changes in these rates over time were measured by subsite. The impact of HPV-positivity on overall survival across six head and neck subsites was assessed using multivariable-adjusted Cox proportional hazards analysis. RESULTS: A total of 121,550 patients were included. Of this cohort, 87,575 (72.1%) were tested for HPV, with the oropharynx (55,049/64,158; 85.8%) displaying the highest rates of testing and the sinonasal tract (1519/2853; 53.2%) displaying the lowest testing rates. Of the 86,136 with a definitive result, 46,878 (54.4%) were HPV-positive, with the oropharynx (40,313/54,205; 74.4%) displaying the highest rates of HPV-positivity and the oral cavity (1818/11,505; 15.8%) displaying the lowest. HPV-positive malignancy was associated with significantly improved adjusted overall survival in the oropharynx (HR = 0.42 [95% CI: 0.43-0.47]), oral cavity (HR = 0.86 [95% CI: 0.79-0.95]), sinonasal tract (HR = 0.63 [95% CI: 0.48-0.83]), larynx (HR = 0.78 [95% CI: 0.71-0.87]), and hypopharynx (HR = 0.56 [95% CI: 0.48-0.66]), but not the nasopharynx (HR = 0.93 [95% CI: 0.77-1.14]). CONCLUSION: HPV testing rates were significantly lower in non-oropharyngeal subsites. This is relevant as HPV-associated disease displayed significantly improved overall survival in both the oropharynx and four of five non-oropharyngeal subsites. While validation with prospective studies is necessary, these findings may warrant HPV testing in all HNSCC subsites.

Thyroid Ethanol and Radiofrequency Ablation: A Call for Patient-Friendly Online Resources.

INTRODUCTION: The multiple treatment options available to patients with thyroid nodules can generate uncertainty and confusion. Radiofrequency ablation (RFA) and ethanol ablation (EA) are two alternative modalities to manage thyroid nodules. As patients more frequently utilize online resources to guide their decision-making, the quality of such resources must be evaluated. The goal of this study was to assess the quality of online patient materials relating to RFA and EA compared to standard thyroidectomy. METHODS: The terms "thyroidectomy," "thyroid radiofrequency ablation," and "thyroid ethanol ablation" were searched on Google. Flesch Reading Ease (FRE), Flesch-Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), and Patient Education Materials Assessment Tool (PEMAT) understandability and actionability were calculated for each website. Statistical analysis was conducted on SPSS Statistics. Google trends were used to determine search interest for each term (May 2016 - May 2021). RESULTS: Of the 77 websites that met our inclusion criteria (30 thyroidectomy sites, 30 RFA sites, and 17 EA sites), the average FRE, FKGL, and SMOG scores of the RFA websites were significantly worse than those of the thyroidectomy websites (p < 0.05). The FKGL and SMOG scores of the EA websites were significantly worse than those of the thyroidectomy websites (p < 0.05). The average understandability and actionability scores for thyroidectomy websites were significantly higher than those of RFA and EA websites (p < 0.05). CONCLUSION: Ablation websites have lower search interest, readability, validity, understandability, and actionability scores in comparison to traditional thyroidectomy websites. Our findings emphasize the need to consider readability and PEMAT scores when developing online educational resources for ablative alternatives to thyroidectomy to allow for greater patient accessibility.

Outcomes of Supracricoid Partial Laryngectomy Performed in the United States: A Systematic Review.

OBJECTIVE: The primary objective of this study was to evaluate oncologic outcomes of all published cases of supracricoid partial laryngectomy (SCPL) performed in the United States. The secondary objective was to assess the functional outcomes associated with this procedure. REVIEW METHODS: A systematic review of PubMed, SCOPUS, and Embase for all English-language studies pertaining to SCPL performed in the United States was conducted until August 2021. Primary outcomes included disease-specific survival (DSS), overall survival, and local recurrence rate. Secondary outcomes included larynx preservation rate, gastrostromy tube dependency, days to gastrostomy tube removal, decannulation rate, and days to decannulation. RESULTS: A total of six studies were included in the analysis. A total of 113 patients (58.5%) underwent SCPL surgery as a primary treatment method whereas 80 patients (41.5%) underwent SCPL as salvage surgery. The 5-year DSS rates were 87.8% and 100% for primary and salvage procedures, respectively. Approximately 10.3% of patients undergoing a salvage SCPL procedure experienced a local recurrence whereas only 1.85% of primary SCPL procedures resulted in local recurrence. The rates of decannulation following primary and salvage SCPL were 92.7% and 88.1%, respectively. With regard to swallowing, primary and salvage SCPL procedures demonstrated comparably low postoperative gastrostomy tube dependency rates of 3.66% and 4.76%, respectively. CONCLUSIONS: SCPL performed in the United States is an effective surgical technique that produces excellent outcomes in qualifying patients, thus validating its viability as an organ-preserving surgical alternative. Laryngoscope, 134:3003-3011, 2024.

Diagnostic Difficulties of Plunging Ranula: A Review of 18 Cases.

OBJECTIVE(S): Despite advancements in imaging techniques and cytological analysis, plunging ranula remains a challenging surgical, radiologic, and pathologic phenomenon. Of the 18 patients we evaluated at our institution, we highlight three cases that illustrate the high rate of misleading imaging and cytological results when assessing plunging ranula. METHODS: Imaging results, biopsy findings, operative techniques, and pathological reports were reviewed from patients who had either a preoperative or postoperative diagnosis of ranula and underwent surgery by a single head and neck surgeon at a tertiary care center. RESULTS: Of the 18 identified patients, computed tomography was correct on preoperative imaging 73% of the time and magnetic resonance imaging was correct on preoperative imaging 71% of the time. Two patients underwent preoperative ultrasound and their ultrasound reports did not accurately diagnose the presence of a ranula. Two patients underwent preoperative fine needle aspiration biopsy due to inconclusive preoperative imaging, in which results suggested either a ranula or epidermal cyst. Both ultimately did not match the final pathology. Three of eighteen patients (17%) underwent an inappropriate initial surgery due to incorrect imaging diagnoses and/or biopsy findings. CONCLUSION: Despite use of preoperative modalities to distinguish plunging ranula from other cystic floor of mouth lesions, surgeons must be aware that no workup modality is fully precise. The potential for revision surgery must be included in all preoperative discussions for presumed plunging ranula. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:2689-2696, 2024.

Frozen Section Timeout: Pilot Study to Reconcile Margins Using 3D Resected Specimen and Defect Scans.

OBJECTIVE: Opportunities exist to improve intraoperative communication and documentation of resection margin details. We instituted a "frozen section timeout" that centers around visualization of the paired resection specimen and surgical defect-facilitating effective, bidirectional exchange of information. METHODS: We designed an interactive form for use during the "frozen section timeout" including annotated 3D virtual models of the resected specimen and surgical defect, plus a "line-item" table for primary and supplemental margin results. The "timeout" was conducted over a Zoom call between the operating room and frozen section laboratory. The form was simultaneously projected and discussed while all members of the surgical care team stopped activities. Nurses, co-surgeons, and all other members of the surgical team were encouraged to take part in this process. RESULTS: Twenty-six frozen section timeouts were conducted during head and neck surgeries in the Department of Otolaryngology at Mount Sinai West Hospital. These timeouts were facilitated by the lead surgeon, and all other activities were halted to ensure that critical information was shared, documented, and agreed upon. During the timeout, the annotated specimen and defect scans were displayed, clearly demonstrating the at-risk margins and the corresponding location and breadth of supplemental margins harvested. CONCLUSION: Incorporating a frozen section timeout can improve intraoperative communication, increase transparency, and potentially eliminate uncertainty regarding margin status and tumor clearance. Visualization of at-risk margins and the corresponding location and breadth of supplemental margins promises an unprecedented level of documentation and understanding. This novel technique can establish a new and improved standard of care. LEVEL OF EVIDENCE: NA Laryngoscope, 134:725-731, 2024.

Thyroid cancer necrosis not evident on imaging: A cautionary case series on poorly differentiated thyroid carcinoma diagnosed only on final pathology.

OBJECTIVE: Poorly-differentiated thyroid cancer (PDTC) is a highly aggressive malignancy which is recently defined and understudied in the radiologic literature. Necrosis is a key histopathologic criterion for the diagnosis of PDTC. We illustrate the current difficulty in accurate identification of histopathologic necrosis on preoperative imaging. METHODS: A series of seven patients with the final diagnosis of PDTC from our institution were identified. Multimodality preoperative imaging was analyzed by two head and neck radiologists. Final pathology reports were queried confirming histopathologic evidence of necrosis. RESULTS: Patients presented with a wide range of preoperative imaging features. A consistent imaging appearance confirming necrosis was not identified. All patients were subsequently upstaged to PDTC following final pathological analysis. CONCLUSION: A lack of definitive evidence of necrosis on preoperative imaging does not exclude the possibility of PDTC. We demonstrate the need for further research to establish a clear methodology for the preoperative diagnosis of PDTC.

iPad Annotation of 3D Surgical Models Using Procreate®: Novel Documentation of Supplemental Margins.

We present a novel, efficient approach to demonstrating supplemental margins during oncologic resection. Surgeons and pathologists annotated 10 virtual models of surgical defects and resection specimens in 3D using an iPad-based application, Procreate®. Incorporating this method into the surgical workflow can improve interdepartmental communication and provide visual documentation of surgical steps taken to address at-risk margins. Laryngoscope, 2023.

Negative Predictive Value of Circulating Tumor Tissue Modified Viral (TTMV)-HPV DNA for HPV-driven Oropharyngeal Cancer Surveillance.

PURPOSE: Human papillomavirus (HPV) is causally linked to oropharyngeal squamous cell carcinoma (OPSCC). Consensus guidelines recommend clinical exams and imaging in decreasing frequency as part of posttreatment surveillance for recurrence. Plasma tumor tissue modified viral (TTMV)-HPV DNA testing has emerged as a biomarker which can inform disease status during surveillance. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved 543 patients who completed curative-intent therapy for HPV-associated OPSCC between February 2020 and January 2022 at eight U.S. cancer care institutions. We determined the negative predictive value (NPV) of TTMV-HPV DNA for recurrence when matched to physician-reported clinical outcome data (median follow-up time: 27.9 months; range: 4.5-154). RESULTS: The cohort included mostly men with a median age of 61 who had locoregionally advanced disease. HPV status was determined by p16 positivity in 87% of patients, with a positive HPV PCR/ISH among 55%; while pretreatment TTMV-HPV DNA status was unknown for most (79%) patients. Patients had a mean of 2.6 tests and almost half had three or more TTMV-HPV DNA results during surveillance. The per-test and per-patient sensitivity of the assay was 92.5% [95% confidence interval (CI): 87.5-97.5] and 87.3% (95% CI: 79.1-95.5), respectively. The NPV for the assay was 99.4% (95% CI: 98.9-99.8) and 98.4% (95% CI: 97.3-99.5), respectively. CONCLUSIONS: TTMV-HPV DNA surveillance testing yields few false negative results and few missed recurrences. These data could inform decisions on when to pursue reimaging following first disease restaging and could inform future surveillance practice. Additional study of how pretreatment TTMV-HPV DNA status impacts sensitivity for recurrence is needed.

Performance of Liquid Biopsy for Diagnosis and Surveillance of Human Papillomavirus-Associated Oropharyngeal Cancer.

Importance: There is growing interest in the use of circulating plasma tumor human papillomavirus (HPV) DNA for diagnosis and surveillance of patients with HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). Recent advances in the assays, combining the identification of circulating HPV tumor DNA and tumor DNA fragment analysis (tumor tissue-modified viral [TTMV]-HPV DNA), have been shown to be highly accurate. However, use of these newer techniques has been limited to small cohort studies and clinical trials. Objective: To establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary clinical setting. Design, Setting, and Participants: This retrospective observational cohort study included patients with OPSCC who underwent TTMV-HPV DNA testing between April 2020 and September 2022 during the course of routine clinical care. For the diagnosis cohort, patients with at least 1 TTMV-HPV DNA measurement prior to initiation of primary therapy were included. Patients were included in the surveillance cohort if they had at least 1 TTMV-HPV DNA test performed after completion of definitive or salvage therapy. Main Outcomes and Measures: Per-test performance metrics, including sensitivity, specificity, positive predictive value, and negative predictive value, for TTMV-HPV DNA testing. Results: Of 399 patients included in the analysis, 163 were in the diagnostic cohort (median [IQR] age, 63 [56-68.5] years; 142 [87.1%] male), and 290 were in the surveillance cohort (median [IQR] age, 63 [57-70] years; 237 [81.7%] male). Of the 163 patients in the diagnostic cohort, 152 (93.3%) had HPV-associated OPSCC while 11 (6.7%) had HPV-negative OPSCC. The TTMV-HPV DNA sensitivity in pretreatment diagnosis was 91.5% (95% CI, 85.8%-95.4% [139 of 152 tests]), and the specificity was 100% (95% CI, 71.5%-100% [11 of 11 tests]). In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. A total of 23 patients had molecularly confirmed pathologic recurrences. The TTMV-HPV DNA test demonstrated sensitivity of 88.4% (95% CI, 74.9%-96.1% [38 of 43 tests]) and specificity of 100% (95% CI, 99.3%-100% [548 of 548 tests]) in detecting the recurrences. Positive predictive value was 100% (95% CI, 90.7%-100% [38 of 38 tests]), and negative predictive value was 99.1% (95% CI, 97.9%-99.7% [548 of 553 tests]). The median (range) lead time from positive TTMV-HPV DNA test to pathologic confirmation was 47 (0-507) days. Conclusions and Relevance: This cohort study demonstrated that when evaluated in a clinical setting, the TTMV-HPV DNA assay demonstrated 100% specificity in both diagnosis and surveillance. However, the sensitivity was 91.5% for the diagnosis cohort and 88.4% for the surveillance cohort, signifying that nearly 1 in 10 negative tests among patients with HPV-associated OPSCC was a false negative. Additional research is required to validate the assay's performance and, if validated, then further research into the implementation of this assay into standard clinical practice guidelines will be required.

Impact of Sternothyroid Muscle Division on Patient-Reported Voice Outcomes After Thyroid Surgery: A Prospective Study.

OBJECTIVE: Division of the sternothyroid muscle during thyroidectomy is a widely accepted surgical technique to provide improved exposure of the thyroid gland, thus facilitating the ligation of superior pole vessels and identification of the laryngeal nerves. However, few have examined the impact on voice outcomes. We evaluate the impact of sternothyroid muscle division on patient-perceived voice outcomes after thyroidectomy. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary academic institution. METHODS: A prospective cohort study was conducted comparing pre- and postoperative voice outcome data after thyroidectomy, measured using Voice Handicap Index-10. The cohort of 109 patients underwent lobectomy or total thyroidectomy by a single surgeon at 1 institution. The sternothyroid muscle was fully divided in all surgeries. The integrity of the recurrent laryngeal and external branches of the superior laryngeal nerve was assessed using intraoperative nerve monitoring and postoperative laryngoscopy. Pre- and postoperative Voice Handicap Index-10 scores were compared. RESULTS: No statistically significant difference was found between total pre- and postoperative Voice Handicap Index-10 scores (µpreop = 1.92, µpostop = 1.83, p = .87). There were no questions yielding statistically significant responses between pre- and postoperative groups. This was consistent regardless of whether the sternothyroid muscle was cut unilaterally or bilaterally. Men showed a statistically significant improvement in score after surgery. CONCLUSION: These findings support no difference in postoperative voice outcomes after the intraoperative division of the sternothyroid muscle. This supports the usage of this technique as a safe means to facilitate exposure during thyroid surgery and will serve as important information to guide intraoperative surgical decision-making.

Frozen Section Analysis in Head and Neck Surgical Pathology: A Narrative Review of the Past, Present, and Future of Intraoperative Pathologic Consultation.

Frozen section has remained the diagnostic gold standard for intraoperative pathological evaluation of surgical margins for head and neck specimens. While achieving tumor-free margins is of utmost importance to all head and neck surgeons, in practice, there are numerous debates and a lack of standardization for the role and method of intraoperative pathologic consultation. This review serves as a summary guide to the historical and contemporary practice of frozen section analysis and margin mapping in head and neck cancer. In addition, this review discusses current challenges in head and neck surgical pathology, and introduces 3D scanning as a groundbreaking technology to bypass many of the pitfalls in the current frozen section workflow. The ultimate goal for all head and neck pathologists and surgeons should be to modernize practices and take advantage of new technology, such as virtual 3D specimen mapping techniques, that improves the workflow for intraoperative frozen section analysis.

Neutrophil-to-lymphocyte ratio as a predictor of surgical outcomes in head and neck cancer.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is a biomarker of systemic inflammation that is associated with adverse oncologic and surgical outcomes. We investigated the use of NLR as a prognostic indicator of complications of head and neck cancer (HNC) surgeries. METHODS: We conducted a retrospective study of 11 187 Veterans who underwent HNC surgery between 2000 and 2020. We calculated preoperative NLR values and fit logistic regression models adjusting for potential confounding factors, comparing high-NLR patients to low-NLR patients. RESULTS: The cohort had a median age of 63 and was 98% men. High-NLR patients had increased odds of 30-day mortality (p < 0.001), having 1+ perioperative complications (p < 0.001), sepsis (p = 0.03), failure to wean from mechanical ventilation (p = 0.04), pneumonia (p < 0.001), and pulmonary embolism (p = 0.02) compared with low-NLR patients. CONCLUSION: NLR was a robust, independent predictor of 30-day mortality, having 1+ surgical complications, sepsis, failure to wean from mechanical ventilation, pneumonia, and pulmonary embolism.

WPOI-5: Accurately Identified at Intraoperative Consultation and Predictive of Occult Cervical Metastases.

BACKGROUND: Frozen section analysis of oral cancer specimens is ideal for assessing margin distances and depth of invasion (DOI); the latter impacts intraoperative decisions regarding elective neck dissection (END). Here, we show that intraoperative determination of worst pattern of invasion (WPOI), specifically WPOI-5, has a high level of accuracy. This relates to our demonstration herein that WPOI-5 predicts occult cervical metastases (OCM) for pT1 oral squamous carcinoma (OSC). METHODS: The presence of OCM was correlated with WPOI in 228 patients with primary T1/T2/cN0 OSC undergoing resection and END. Concordance between intraoperative and final pathology WPOI determination was assessed on 51 cases of OSC. RESULTS: WPOI-5 predicts OCM in pT1 patients, compared with WPOI-4/WPOI-3 (p < 0.0001). Most pT1 WPOI-5 tumors had DOI of 4-5 mm (24/59 or 40.7%). Only two pT1 WPOI-5 tumors had DOI < 4 mm (3.0 and 3.5 mm). If END were performed in this pT1 cohort for all WPOI-5 OSC patients regardless of DOI, OR all OSC patients with DOI ≥ 4 mm regardless of WPOI, then no OCM would be missed (p = 0.017, 100% sensitivity, 29% specificity, 77% positive predictive value, 23% negative predictive value). With respect to intraoperative WPOI-5 determination, the accuracy, sensitivity, and specificity was 92.16, 73.33, and 100.0%, respectively. CONCLUSIONS: DOI ≥ 4 mm is the dominant predictor of OCM. For the rare WPOI-5 OSC with DOI < 4 mm, it is reasonable to suggest that surgeons perform END. WPOI-5 may be accurately determined intraoperatively. As microscopic instruction is needed to accurately assess WPOI-5, a teaching link is included in this manuscript.

Extratumoral invasion: A unique phenomenon of aggressive recurrent oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous carcinomas cause significant morbidity and mortality. Poor prognosticators include lymphovascular and perineural invasion. Extratumoral phenotypes of these histologic findings confer worse prognoses. METHODS: We report eight cases of recurrent oropharyngeal cancer with diffuse extratumoral lymphovascular invasion (ELVI) or extratumoral perineural invasion (EPNI) and review the existing literature. RESULTS: On salvage resection for recurrence following primary radiation or chemoradiation, six patients manifested ELVI and two showed EPNI. These patterns conferred difficulty with complete surgical clearance; final pathologic analysis demonstrated positive margins for all eight patients. The six patients with ELVI were p16+ and the two with EPNI were p16-. Currently, two patients are deceased and six patients are alive at an average follow-up of 17.4 months. Of the six living patients, 2 have a new recurrence and are in hospice while 4 have no evidence of disease. CONCLUSIONS: ELVI and EPNI have received little consideration in the literature as unique histopathologic features of oropharyngeal squamous carcinoma. We present the first series on these adverse extratumoral features in recurrent disease. We call attention to these unique histologic features in the setting of recurrent oropharyngeal cancer to encourage others to track the results of therapeutic intervention and to identify successful strategies for treatment.

A rare case of canalicular adenoma in the parotid gland: Highlighting diagnostic limitations of fine-needle aspiration.

BACKGROUND: Canalicular adenoma is a rare, benign tumor of primarily salivary gland origin that presents mostly in the upper lip. However, there are only six reports in the English literature detailing canalicular adenoma of the parotid gland, none of which discuss discrepancy between preoperative cytology and surgical pathology. In this report, we present a rare case of parotid gland canalicular adenoma where preoperative ultrasound-guided fine-needle aspiration (USFNA) suggested malignancy. The patient was treated with deep lobe parotidectomy due to the FNA results and her multiple comorbidities. However, her tumor may have been treated with observation alone if canalicular adenoma had been suspected prior to surgery. MAIN FINDINGS: A 59-year-old female with a history of heart and lung disease presented with a 1.6 cm well defined, enhancing lesion involving the superficial portion of the right parotid gland. This lesion was incidentally noted on CT angiography (CTA) of the neck and chest. The well-defined characteristics of this lesion on CT imaging suggested benign neoplasm. However, USFNA results were suggestive of a malignant parotid lesion. The patient subsequently underwent right deep lobe parotidectomy with facial nerve dissection and superficial musculoaponeurotic system (SMAS) rotational flap reconstruction. Surgical pathology and immunohistochemistry yielded a final diagnosis of benign canalicular adenoma. CONCLUSIONS: USFNA diagnosis of CA is extremely difficult due to its low-grade neoplastic cells mimicking neoplastic cells in other benign and malignant tumors of the head and neck. FNA remains a useful tool for assessing malignancy risk, but the results always have some level of uncertainty and do not provide sufficient detail. Therefore, FNA results should be interpreted in concert with imaging and patients' medical history. Cytopathologists can also report salivary gland FNA results in a more uniform and detailed manner by utilizing the Milan System for Reporting Salivary Gland Cytopathology (MSRSGC).

The Sinai Robotic Surgery Trial in HPV-related oropharyngeal squamous cell carcinoma (SIRS 2.0 trial) - study protocol for a phase II non-randomized non-inferiority trial.

Background: Human papillomavirus associated oropharyngeal squamous cell carcinoma (HPVOPSCC) usually affects a younger patient population. As such, the risk for long term toxicity associated with therapy is an important consideration. Multiple trials focused on de-escalation of therapy to preserve survival outcomes while minimizing treatment toxicity are currently in progress, however the question of which patients are ideal candidates for de-escalation remains unanswered. Circulating tumor DNA (cfHPVDNA) has emerged as a means of monitoring disease in patients with HPVOPSCC. Undetectable postoperative cfHPVDNA levels portend a better prognosis and by extension, may identify ideal candidates for de-escalation therapy. We propose an overview and rationale for a new institutional clinical trial protocol focusing on the use of cfHPVDNA to risk stratify patients for adjuvant therapy. We hypothesize that many surgical patients currently receiving radiation therapy may be clinically observed without adjuvant therapy. Methods: Patients with measurable cfHPVDNA and clinically resectable HPVOPSCC will undergo TORS resection of tumors and neck dissection. Patients with undetectable cfHPVDNA at 3 weeks post-op will be allocated to low or high-risk treatment protocol groups. The low risk group consists of patients with <4 positive lymph nodes, ≤2 mm extranodal extension (ENE), and perineural invasion (PNI) or lymphovascular invasion (LVI) alone. The high-risk group is made up of patients with ≥4 positive lymph nodes, gross ENE, positive margins, N2c disease and/or the combination of both PNI and LVI. The low-risk group will be allocated to an observation arm, while the high-risk group will receive 46 Gy of adjuvant radiotherapy and weekly cisplatin therapy. The primary outcome of interest is 2-year disease recurrence with secondary outcomes of 2-year disease free survival, locoregional control, overall survival, and quality of life measures. A sample of 126 patients in the low-risk group and 73 patients in the high-risk group will be required to evaluate non-inferiority to the standard of care. Discussion: This study will provide much needed recurrence and survival data for patients that undergo primary TORS followed by observation or de-escalated adjuvant therapy. Additionally, it will help delineate the role of cfHPVDNA in the risk stratification of patients that undergo treatment de-intensification.