Malignant Epithelioid Mesenchymal Neoplasm with FUS::CREM Gene Fusion Arising in the Tongue: A Case Report Detailing Clinicopathological, Imaging, and Molecular Features.

FUS::CREM fusion is a distinct primary driver in rare neoplasms of the head and neck and other anatomic sites. Herein, we describe the clinicopathological, imaging, and molecular features of a malignant epithelioid mesenchymal neoplasm harboring FUS::CREM fusion, arising in the tongue of a 46-year-old male. Clinically, the patient presented with a left upper neck mass. Imaging revealed a 4.0 cm mass at the left base of tongue. Histologically, the tumor consisted of sheets of loosely cohesive, small round to ovoid cells with moderate cytoplasm, small nuclei with coarse chromatin, frequent nuclear pseudoinclusions, and dense peripheral lymphoplasmacytic and histiocytic infiltrates. Malignant features, including tumor necrosis, perineural invasion, and increased mitotic activity were observed; however, lymphovascular invasion was absent with no evidence metastatic disease in the examined lymph nodes. A comprehensive panel of immunohistochemical stains showed positivity for synaptophysin and ALK, with negative results for all other markers. RNA-based next-generation sequencing using anchored multiplex polymerase chain reaction (PCR) was performed and detected FUS::CREM fusion gene. The patient was treated by excision and postsurgical chemoradiation with no evidence of recurrence after four months. Additional cases supported by comprehensive clinical data collected over an extended period are necessary to precisely characterize epithelioid mesenchymal neoplasms harboring FUS::CREM fusion in the head and neck.

Modified Technique for Retrograde Placement of the Tracheoesophageal Voice Prosthesis in the Office.

For total laryngectomy patients with tortuous tracheoesophageal puncture (TEP) tracts, anterograde placement of the voice prosthesis can be challenging. This article describes an updated and straightforward technique for in-office retrograde placement of the voice prosthesis in patients with such challenging TEP tracts. Laryngoscope, 2024.

Salvage surgery for recurrent or residual hypopharyngeal squamous cell carcinoma: A systematic review.

BACKGROUND: This systematic review aggregates the data of studies that include site-specific analyses of patients undergoing salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma. METHODS: The primary outcomes are disease-free, disease-specific, and overall survival (DFS, DSS, and OS, respectively). Secondary outcomes include complications and postoperative feeding requirements. RESULTS: Fifteen studies met the inclusion criteria with a total of 442 patients. Two-year DFS is reported from 30.0 to 50.0% and 5-year DFS ranges from 15.0 to 57.1%. Five-year DSS ranges from 28.0 to 57.1%. Two-year OS ranges from 38.8 to 52.0% and 5-year OS ranges from 15.5 to 57.1%. Complications include pharyngocutaneous fistula (0.0-71.4%), carotid artery rupture (2.9-13.3%), and stomal stenosis (4.2-20.0%). Complete oral feeding achieved following surgery ranges from 61.9 to 100.0%, while complete gastrostomy tube dependence ranges from 0.0 to 28.6%. CONCLUSIONS: Salvage surgery for residual or recurrent hypopharyngeal squamous cell carcinoma has a relatively high complication rate and should be offered to patients with the understanding of a guarded prognosis.

FNA of Meningioma with Rhabdoid Features Presenting as a Lateral Neck Mass.

Primary meningioma at extracranial head and neck sites is uncommon. Since fine needle aspiration (FNA) is often the first line diagnostic modality for the evaluation of masses in the head and neck, extracranial meningiomas can create a significant diagnostic pitfall for FNA. We report a case of meningioma with rhabdoid features and BAP1 loss in a 26-year-old woman, presenting as a large neck mass along the carotid sheath. FNA biopsy of the mass demonstrated a highly cellular specimen with clusters of uniform, epithelioid cells with round to ovoid nuclei and moderate nuclear to cytoplasmic ratio. An extensive immunohistochemical panel performed on cell block sections showed that the tumor cells were weakly EMA positive, progesterone receptor was focally positive, and SSTR2A was diffuse and strongly positive. BAP1 immunohistochemistry showed a diffuse loss of expression in the tumor cells. After the cytologic diagnosis of meningioma, a tissue biopsy was performed, and the diagnosis of meningioma with rhabdoid features and BAP1 loss was confirmed. We also perform a literature review of meningioma cases presenting as a neck mass and evaluated by FNA. Our case highlights the significant diagnostic challenges that can be caused by extracranial meningiomas on FNA and the importance of ancillary studies to avoid diagnostic pitfalls.

Early Weight-Bearing After Fibula Free Flap Surgery.

Importance: Despite the widespread use of fibula free flap (FFF) surgery for head and neck reconstruction, there are no studies assessing if early weight-bearing (EWB) affects postoperative recovery, and the timing of weight-bearing initiation following FFF surgery varies considerably across institutions. Therefore, it is important to understand the effect of EWB in these patients and whether it could improve postoperative recovery. Objective: To assess the association of EWB after FFF surgery with donor-site complications, length of stay, and discharge to home status. Design, Setting, and Participants: This retrospective cohort study took place at Massachusetts Eye and Ear, a single tertiary care institution in Boston, Massachusetts. A total of 152 patients who received head and neck reconstruction with a fibula osteocutaneous free flap between January 11, 2010, and August 11, 2022, were included. Exposure: EWB on postoperative day 1 vs non-EWB on postoperative day 2 or later. Main Outcomes and Measures: Patient characteristics, including demographic characteristics and comorbidities, surgical characteristics, donor-site complications, length of stay, and discharge disposition, were recorded. Descriptive statistics and multivariate logistic regressions were used to compute effect sizes and 95% CIs to compare postoperative outcomes in EWB and non-EWB groups. Results: A total of 152 patients (median [IQR] age, 63 [55-70] years; 89 [58.6%] male) were included. The median (IQR) time to postoperative weight-bearing was 3 (1-5) days. Among all patients, 14 (9.2%) had donor-site complications. EWB on postoperative day 1 was associated with shorter length of stay (adjusted odds ratio [AOR], 0.10; 95% CI, 0.02-0.60), increased rate of discharge to home (AOR, 7.43; 95% CI, 2.23-24.80), and decreased donor-site complications (AOR, 0.11; 95% CI, 0.01-0.94). Conversely, weight-bearing 3 or more days postoperatively was associated with an increased risk of pneumonia (AOR, 6.82; 95% CI, 1.33-34.99). Conclusions and Relevance: In this cohort study, EWB after FFF surgery was associated with shorter length of stay, increased rate of discharge to home, and decreased donor-site complications. These findings support the role of early mobilization to optimize postoperative recovery after FFF surgery.

Predictors of multiple dilations and functional outcomes after total laryngectomy and laryngopharyngectomy.

BACKGROUND: Following total laryngectomy (TL) or laryngopharyngectomy (TLP), patients may develop strictures that require multiple dilations to treat. However, the risk factors associated with dysphagia refractory to a single dilation are unknown. METHODS: Single-institution retrospective review of patients who underwent at least one stricture dilation after TL/TLP between March 2013 and March 2022. RESULTS: A total of 49 patients underwent stricture dilation after TL/TLP. Thirty-five (71%) underwent multiple dilations. Pharyngocutaneous fistula, primary chemoradiation therapy, and a shorter time interval from TL/TLP to first dilation were independently associated with dysphagia requiring multiple dilations. Patients in the multiple dilations group had a higher rate of limited diet and G-tube dependence compared to patients in the single dilation group. CONCLUSIONS: Shorter time interval to stricture formation is a prognostic indicator of the need for multiple dilations following TL/TLP. Patients requiring multiple dilations are at increased risk of persistent dysphagia long-term.

Depth of resection predicts loss of tongue tip sensation after partial glossectomy in oral tongue cancer: A pilot study.

OBJECTIVE(S): To characterize the change in sensory function following partial glossectomy for oral tongue cancer (OTC) and to identify predictors of loss of tongue-tip sensation (LoTTS). MATERIALS AND METHODS: Patients with at least three months follow-up after partial glossectomy for primary OTC were included. All patients underwent a qualitative tongue sensation assessment and an objective tongue sensory exam of the native tongue tip. Additional details regarding the oncologic resection, surgical reconstruction, and pathological stage were collected. Multiple linear and logistic regressions were used for statistical analysis. RESULTS: Sixty-four patients were enrolled, including 34 (53%) men with a median age of 65 at enrollment. Ten (15%) patients reported LoTTS. Increased depth of resection (DOR) was an independent predictor of LoTTS on multivariate analysis, with an increased risk at a threshold of 1.3 cm. LoTTS was also associated with worse subjective quality of life and perceptive speech performance in our qualitative tongue assessment. CONCLUSIONS: In this pilot study, we found that DOR is a critical prognostic factor in predicting post treatment function. Patients with an increased DOR, particularly above 1.3 cm, are at greatest risk of LoTTS and associated morbidity. These findings may be used to predict post-operative sensory deficits, manage patients' expectations, and optimize the reconstructive approach. Future studies are needed to validate and replicate our results.

Regional Flap Donor Sites in Head and Neck Reconstruction.

Regional flaps are vital to head and neck reconstruction, allowing surgeons to harvest numerous reliable flaps without the need for microvascular anastomosis. These flaps are very useful in cases of vascular depletion and may prove superior to free flaps as a primary option in certain circumstances. Numerous harvest options are available, and the described harvest techniques are safe and straightforward for an experienced reconstructive surgeon to learn. Donor site morbidity is variable depending on flap selection but minimal in many cases. Regional flaps are an excellent option in resource-limited settings or when minimizing reoperation is a high priority.

Comparison of patient-reported upper extremity disability following free flaps in head and neck reconstruction: A systematic review and meta-analysis.

BACKGROUND: Comparisons of patient-reported donor site morbidity based on the Disabilities in Arm, Shoulder, and Hand (DASH) instrument across upper trunk free flaps in head and neck surgery, including radial forearm (RFFF), osteocutaneous radial forearm (OCRFF), scapular tip (STFF), and serratus anterior (SAFF) free flaps, may help inform donor tissue selection. METHODS: In this meta-analysis, 12 studies were included and the primary outcome was average DASH score. RESULTS: The pooled DASH scores were 12.14 (95% CI: 7.40-16.88) for RFFF (5 studies), 17.99 (11.87-24.12) for OCRFF (2 studies), 12.19 (8.74-15.64) for STFF (3 studies), and 16.49 (5.92-27.05) for SAFF (2 studies) and were not significantly different. CONCLUSIONS: Results suggest that patients generally function well, with minimal to mild donor site morbidity, when assessed at an average of 20 months after flap harvest. These results are based on few effects from primarily retrospective studies of fair quality, and further research is needed.

Development and Content Validity of a Novel Patient-Reported Outcome Measure for Total Laryngectomy: The LARY-Q.

OBJECTIVES: To develop a patient-reported outcomes measure (PROM) for total laryngectomy. STUDY DESIGN: Qualitative interviews with a purposive sample of patients with total laryngectomy, followed by cognitive debriefing interviews with patients and expert feedback. METHODS: Concept elicitation was performed using in-depth qualitative interviews with a purposive sample of patients who had undergone total laryngectomy. Patients were recruited from head and neck surgery and speech-language pathology clinics as well as via laryngectomy support groups. Interviews were conducted, recorded, transcribed, and coded, resulting in a conceptual framework and item pool. Using the item pool, preliminary scales were drafted. The scales were revised iteratively over 5 rounds using feedback from cognitive interviews with patients and multi-institutional and multi-disciplinary expert feedback. RESULTS: A total of 15 patients with total laryngectomy (mean age 68 years, range 57-79) were interviewed resulting in 1555 codes. The codes were used to form a conceptual framework grouped into top-level domains of stoma, function, health-related quality of life, devices, and experience of care. Items were used to form 15 preliminary scales that were revised over five rounds of cognitive debriefing interviews (n = 9 patients) and expert feedback (n = 17 experts). The field-test version of the LARY-Q has 18 scales and 277 items in total. CONCLUSIONS: The LARY-Q is a novel PROM designed to assess outcomes associated with total laryngectomy. The next step involves a field test study with a heterogenous sample of patients to assess the psychometric properties of the LARY-Q and perform item reduction.

Surgical factors affecting regionally metastatic cutaneous squamous cell carcinoma to the parotid gland.

BACKGROUND: Understanding the impact of surgical treatment on regionally metastatic cutaneous squamous cell carcinoma (cSCC). METHODS: Retrospective series of 145 patients undergoing parotidectomy and neck dissection for regionally metastatic cSCC to the parotid. Overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) analyzed over 3 years. Multivariate analysis was completed using Cox proportional hazard models. RESULTS: OS was 74.5%, DSS was 85.5% and DFS was 64.8%. On multivariate analysis, immune status (HR = 3.225[OS], 5.119[DSS], 2.071[DFS]) and lymphovascular invasion (HR = 2.380[OS], 5.237[DSS], 2.595[DFS]) were predictive for OS, DSS, and DFS. Margin status (HR = 2.296[OS], 2.499[DSS]) and ≥18 resected nodes (HR = 0.242[OS], 0.255[DSS]) were predictive of OS and DSS, while adjuvant therapy was predictive of DSS (p = 0.018). CONCLUSIONS: Immunosuppression and lymphovascular invasion portended worse outcomes in patients with metastatic cSCC to the parotid. Microscopically positive margins and <18 nodes resected are associated with worse OS and DSS, while patients receiving adjuvant therapy had improved DSS.

Comparison of Preoperative DOI Estimation in Oral Tongue Cancer With cN0 Disease.

OBJECTIVE: To understand the accuracy of pre- and intraoperative estimation of tumor depth of invasion (DOI). STUDY DESIGN: A retrospective case-control study. SETTING: Patients who presented at 1 institution with oral tongue squamous cell carcinoma that underwent oncologic resection between 2017 and 2019 were identified. METHODS: Patients that met the inclusion criteria were included. Patients with nodal, distant, or recurrent disease, prior history of head and neck cancer, or preoperative tumor assessment and/or final histopathology that did not include DOI were excluded. Preoperative DOI estimation and technique and pathology reports were obtained. Our primary outcome was the sensitivity and specificity of DOI estimation modalities including full-thickness biopsy (FTB), manual palpation (MP), punch biopsy (PB), and intraoperative ultrasound (IOUS). RESULTS: Tumor DOI was assessed quantitatively preoperatively in 40 patients by FTB (n = 19, 48%), MP (n = 17, 42%), or PB (n = 4, 10%). Additionally, 19 patients underwent IOUS to assess DOI. The sensitivities of FTB, MP, and IOUS for DOI ≥ 4 mm were 83% (confidence interval [CI]: 44%-97%), 83% (CI: 55%-95%), and 90% (CI: 60%-98%), respectively, and the specificities were 85% (CI: 58%-96%), 60% (CI: 23%-88%), and 78% (CI: 45%-94%). CONCLUSION: Our study demonstrated that DOI assessment tools measured had similar sensitivity and specificity in stratifying patients with DOI ≥4 mm, with no statistically superior diagnostic test. Our results support the need for additional research into nodal disease prediction and continued refinement of ND decisions with respect to DOI.

Rate of atypical nodal metastases in surgically treated HPV-associated oropharyngeal squamous cell carcinoma.

BACKGROUND: Understanding of nodal metastasis in patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) is warranted. METHODS: Patients with HPV+ OPSCC who underwent neck dissection (ND) between 2016 and 2021 were reviewed. Pathology reports were reviewed for lymph node (LN) metastases. Noncontiguous metastases were defined as pathologic evidence of level II disease with another involved LN in a noncontiguous neck level. Skip metastases were defined as pathologic lymph node(s) in the neck without disease in level II. RESULTS: One hundred and thirty-one patients underwent levels II-IV ND with a mean (SD) LN yield of 33.3 (±13.5). The rate of atypical metastases in both the therapeutic and elective ND cohort was 5%. The noncontiguous and skip metastases were in level IV (n = 2) and level III (n = 4), respectively. CONCLUSIONS: Skip and noncontiguous metastases were rare in patients with HPV+ OPSCC undergoing surgical treatment. Surgeons may consider a selective ND omitting Level IV in select patients with HPV+ OPSCC undergoing surgery.

Single-cell RNA sequencing identifies a paracrine interaction that may drive oncogenic notch signaling in human adenoid cystic carcinoma.

Salivary adenoid cystic carcinoma (ACC) is a rare, biologically unique biphasic tumor that consists of malignant myoepithelial and luminal cells. MYB and Notch signaling have been implicated in ACC pathophysiology, but in vivo descriptions of these two programs in human tumors and investigation into their active coordination remain incomplete. We utilize single-cell RNA sequencing to profile human head and neck ACC, including a comparison of primary ACC with a matched local recurrence. We define expression heterogeneity in these rare tumors, uncovering diversity in myoepithelial and luminal cell expression. We find differential expression of Notch ligands DLL1, JAG1, and JAG2 in myoepithelial cells, suggesting a paracrine interaction that may support oncogenic Notch signaling. We validate this selective expression in three published cohorts of patients with ACC. Our data provide a potential explanation for the biphasic nature of low- and intermediate-grade ACC and may help direct new therapeutic strategies against these tumors.

Chemoradiation therapy alters the PD-L1 score in locoregional recurrent squamous cell carcinomas of the head and neck.

PD-L1 testing guides therapeutic decision-making for head and neck squamous cell carcinoma (HNSCC). We sought to understand whether chemoradiation therapy (CRT) influences the PD-L1 combined positive score (CPS) and other biomarkers of response to immunotherapy. PD-L1 expression was assessed using immunohistochemistry, and bulk RNA sequencing was performed on 146 HNSCC patients (65 primary sites, 50 paired local recurrences, and 31 paired regional recurrences). PD-L1 was scored using the CPS of ≥1, ≥20, and ≥50. Overall, 98 %, 54 %, and 17 % of HNSCCs had a CPS ≥1, ≥20, and ≥50, respectively. When using a cut-off of ≥1, CRT did not significantly change CPS at the locoregional recurrent site. However, there were significant changes when using CPS ≥20 or ≥50. The CPS changed for 32 % of patients when using a CPS ≥20 (p < 0.001). When using a CPS ≥50, there was a 20-23 % (p = 0.0058-0.00067) discordance rate at the site of locoregional recurrence. Oral cavity cancers had a significantly higher discordant rate than other primary sites for CPS ≥50, 44 % (8/18, p = 0.0058) and 58 % (7/12, p = 0.00067) discordance at the site of local and regional recurrence, respectively. When evaluating the 18 gene IFN-É£ signature predictive of response to anti-PD-1 blockade, there was a statistically significant increase in the IFN-É£ signature in recurrent larynx cancer (p = 0.02). Our study demonstrates that when using a higher cut-off of CPS ≥20 and ≥50, a repeat biopsy may be warranted after CRT for local and regional recurrent HNSCCs.

Multiplexed single-cell analysis of FNA allows accurate diagnosis of salivary gland tumors.

Diagnosing salivary gland tumors (SGTs) through fine-needle aspiration (FNA) biopsies is challenging due to the overlapping cytomorphologic features between benign and malignant tumors. The authors developed an innovative, multiplexed cycling technology for the rapid analyses of single cells obtained from FNA that can facilitate the molecular analyses and diagnosis of SGTs. Antibodies against 29 protein markers associated with 7 SGT subtypes were validated and chemically modified via custom linker-bio-orthogonal probes (FAST). Single-cell homogenates and FNA samples were profiled by FAST cyclic imaging and computational analysis. A prediction model was generated using a training set of 151,926 cells from primary SGTs (N = 26) and validated on a separate cohort (N = 30). Companion biomarker testing, such as neurotrophic tyrosine receptor kinase (NTRK), was also assessed with the FAST technology. The FAST molecular diagnostic assay was able to distinguish between benign and malignant SGTs with an accuracy of 0.86 for single-cell homogenate samples and 0.88 for FNA samples. Profiling of multiple markers as compared to a single marker increased the diagnostic accuracy (0.82 as compared to 0.65-0.74, respectively), independent of the cell number sampled. NTRK expression was also assessed by the FAST assay, highlighting the potential therapeutic application of this technology. Application of the novel multiplexed single-cell technology facilitates rapid biomarker testing from FNA samples at low cost. The customizable and modular FAST-FNA approach has relevance to multiple pathologies and organ systems where cytologic samples are often scarce and/or indeterminate resulting in improved diagnostic workflows and timely therapeutic clinical decision-making.

Head and neck cancer survivorship consensus statement from the American Head and Neck Society.

OBJECTIVES: To provide a consensus statement describing best practices and evidence regarding head and neck cancer survivorship. METHODS: Key topics regarding head and neck cancer survivorship were identified by the multidisciplinary membership of the American Head and Neck Society Survivorship, Supportive Care & Rehabilitation Service. Guidelines were generated by combining expert opinion and a review of the literature and categorized by level of evidence. RESULTS: Several areas regarding survivorship including dysphonia, dysphagia, fatigue, chronic pain, intimacy, the ability to return to work, financial toxicity, lymphedema, psycho-oncology, physical activity, and substance abuse were identified and discussed. Additionally, the group identified and described the role of key clinicians in survivorship including surgical, medical and radiation oncologists; dentists; primary care physicians; psychotherapists; as well as physical, occupational, speech, and respiratory therapists. CONCLUSION: Head and neck cancer survivorship is complex and requires a multidisciplinary approach centered around patients and their caregivers. As survival related to head and neck cancer treatment improves, addressing post-treatment concerns appropriately is critically important to our patient's quality of life. There continues to be a need to define effective and efficient programs that can coordinate this multidisciplinary effort toward survivorship.

Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). METHODS: To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24 hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. RESULTS: In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1 copy/mL by POD 1 (n = 8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350 copies/mL) and remained elevated until adjuvant treatment (n = 3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n = 9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1 mm (P = .0481) and with increasing lymph nodes involved (P = .0453) and were further associated with adjuvant treatment received (P = .0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2 months earlier than clinical detection. CONCLUSIONS: POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. LAY SUMMARY: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1 day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

Cell-Free HPV DNA Provides an Accurate and Rapid Diagnosis of HPV-Associated Head and Neck Cancer.

PURPOSE: HPV-associated head and neck squamous cell carcinoma (HPV+HNSCC) is the most common HPV-associated malignancy in the United States and continues to increase in incidence. Current diagnostic approaches for HPV+HNSCC rely on tissue biopsy followed by histomorphologic assessment and detection of HPV indirectly by p16 IHC. Such approaches are invasive and have variable sensitivity. EXPERIMENTAL DESIGN: We conducted a prospective observational study in 140 subjects (70 cases and 70 controls) to test the hypothesis that a noninvasive diagnostic approach for HPV+HNSCC would have improved diagnostic accuracy, lower cost, and shorter diagnostic interval compared with standard approaches. Blood was collected, processed for circulating tumor HPV DNA (ctHPVDNA), and analyzed with custom ddPCR assays for HPV genotypes 16, 18, 33, 35, and 45. Diagnostic performance, cost, and diagnostic interval were calculated for standard clinical workup and compared with a noninvasive approach using ctHPVDNA combined with cross-sectional imaging and physical examination findings. RESULTS: Sensitivity and specificity of ctHPVDNA for detecting HPV+HNSCC were 98.4% and 98.6%, respectively. Sensitivity and specificity of a composite noninvasive diagnostic using ctHPVDNA and imaging/physical examination were 95.1% and 98.6%, respectively. Diagnostic accuracy of this noninvasive approach was significantly higher than standard of care (Youden index 0.937 vs. 0.707, P = 0.0006). Costs of noninvasive diagnostic were 36% to 38% less than standard clinical workup and the median diagnostic interval was 26 days less. CONCLUSIONS: A noninvasive diagnostic approach for HPV+HNSCC demonstrated improved accuracy, reduced cost, and a shorter time to diagnosis compared with standard clinical workup and could be a viable alternative in the future.