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Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.

Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity's associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed. To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.

BackgroundThe COVID-19 pandemic has required triage and delays in surgical care throughout the world. The impact of these surgical delays on survival for patients with head and neck squamous cell carcinoma (HNSCC) remains unknown.MethodsA retrospective cohort study of 37 730 patients in the National Cancer Database with HNSCC who underwent primary surgical management from 2004 to 2016 was performed. Uni- and multivariate analyses were used to identify predictors of overall survival. Bootstrapping methods were used to identify optimal time-to-surgery (TTS) thresholds at which overall survival differences were greatest. Cox proportional hazard models with or without restricted cubic splines were used to determine the association between TTS and survival.ResultsThe study identified TTS as an independent predictor of overall survival (OS). Bootstrapping the data to dichotomize the cohort identified the largest rise in hazard ratio (HR) at day 67, which was used as the optimal TTS cut-point in survival analysis. The patients who underwent surgical treatment longer than 67 days after diagnosis had a significantly increased risk of death (HR, 1.189; 95% confidence interval [CI], 1.122–1.261; P < 0.0001). For every 30-day delay in TTS, the hazard of death increased by 4.6%. Subsite analysis showed that the oropharynx subsite was most affected by surgical delays, followed by the oral cavity.ConclusionsIncreasing TTS is an independent predictor of survival for patients with HNSCC and should be performed within 67 days after diagnosis to achieve optimal survival outcomes.

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications. Single-cell analysis of head and neck squamous cell carcinoma (HNSCC), specifically from human papillomavirus (HPV)-positive and HPV-negative oropharynx tumors, reveals high levels of inter- and intratumoral heterogeneity. Patterns of HPV gene expression were divergent within HPV-positive tumors, with corresponding functional effects on treatment resistance.

Head and neck cancer is the seventh most common type of cancer worldwide and comprise of a diverse group of tumours affecting the upper aerodigestive tract. Although many different histologies exist, the most common is squamous cell carcinoma. Predominant risk factors include tobacco use, alcohol abuse, and oncogenic viruses, including human papillomavirus and Epstein-Barr virus. Head and neck malignancies remain challenging to treat, requiring a multidisciplinary approach, with surgery, radiotherapy, and systemic therapy serving as key components of the treatment of locally advanced disease. Although many treatment principles overlap, treatment is generally site-specific and histology-specific. This Seminar outlines the current understanding of head and neck cancer and focuses on treatment principles, while also discussing future directions to improve the outcomes of patients with these malignancies.

BackgroundT cell receptor (TCR) signaling profile is a fundamental property that underpins both adaptive and innate immunity in the host. Despite its potential clinical relevance, the TCR repertoire in peripheral blood has not been thoroughly explored for its value as an immunotherapy efficacy biomarker in head and neck squamous cell carcinoma (HNSCC). The purpose of the present study is to characterize and compare the TCR repertoire in peripheral blood mononuclear cells (PBMC) from patients with HNSCC treated with the combination of cetuximab and nivolumab.MethodsWe used the immunoSEQ assay to sequence the TCR beta (TCR-B) chain repertoire from serially obtained PBMC at baseline and during the treatments from a total of 41 patients who received the combination (NCT03370276). Key TCR repertoire metrics, including diversity and clonality, were calculated and compared between patients with different therapy responses and clinical characteristics (eg, human papillomavirus (HPV) status and smoking history). Patient survival outcomes were compared according to patient groups stratified by the TCR-B clonotyping. To confirm the observed patterns in TCR spectrum, samples from patients who achieved complete response (CR) and partial response (PR) were further profiled with the immunoSEQ deep resolution assay.ResultsOur data indicated that the patients who achieved CR and PR had an increased TCR sequence diversity in their baseline samples, this tendency being more pronounced in HPV-negative patients or those with a smoking history. Notably, the CR/PR group had the lowest proportion of patients with oligoclonal TCR clones (2 out of 8 patients), followed by the stable disease group (9 out of 20 patients) and lastly the progressive disease group (7 out of 10 patients). An overall trend toward favorable patient survival was also observed in the polyclonal group. Finally, we reported the shared TCR clones across patients within the same response group, as well as the shared clones by aligning immunoSEQ reads with TCR data retrieved from The Cancer Genome Atlas- head and neck squamous cell carcinoma (TCGA-HNSC) cohort.ConclusionsOur data suggest that, despite the great clinical heterogeneity of HNSCC and the limited responders in the present cohort, the peripheral TCR repertoires from pretreatment PBMC may be developed as biomarkers for the benefit of immunotherapy in HNSCC.

Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. Methods A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. Results 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. Conclusions Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.

Cultured cell lines are the workhorse of cancer research, but the extent to which they recapitulate the heterogeneity observed among malignant cells in tumors is unclear. Here we used multiplexed single-cell RNA-seq to profile 198 cancer cell lines from 22 cancer types. We identified 12 expression programs that are recurrently heterogeneous within multiple cancer cell lines. These programs are associated with diverse biological processes, including cell cycle, senescence, stress and interferon responses, epithelial–mesenchymal transition and protein metabolism. Most of these programs recapitulate those recently identified as heterogeneous within human tumors. We prioritized specific cell lines as models of cellular heterogeneity and used them to study subpopulations of senescence-related cells, demonstrating their dynamics, regulation and unique drug sensitivities, which were predictive of clinical response. Our work describes the landscape of heterogeneity within diverse cancer cell lines and identifies recurrent patterns of heterogeneity that are shared between tumors and specific cell lines. Single-cell RNA-seq of a collection of 200 cancer cell lines finds common, recurrent heterogeneous expression programs, which also are found in patient samples and are linked to cell state and drug sensitivity.

Background Segmental mandibulectomy and mandibular reconstruction are often performed for various benign and malignant head and neck conditions. Standard of care reconstruction involves titanium plate fixation with tissue transfer. The advent of computer-aided design and manufacturing (CAD/CAM) has enhanced aesthetic and functional outcomes in mandibular reconstruction by enabling patient-specific solutions like 3D-printed anatomic models. At an increasing number of institutions, these solutions can be produced in-house via point-of-care manufacturing. Since little has been published on the accuracy and outcomes of this approach, this study sought to evaluate the reconstructive accuracy and clinical outcomes of patients who received in-house patient-specific mandible models. Methods A retrospective chart review was conducted of 44 patients from a large midwestern academic medical center who received point-of-care patient-specific 3D printed models to assist in segmental mandibulectomy and reconstruction from December 2020 to June 2022. CAD/CAM models were produced from pre- and post-operative CT scans. Pre- and post-operative scans were aligned using a novel reference landmark—the maxilla. Measurements were taken by two different researchers at the mandibular condyles, coronoids, angles as well as a plane from the maxilla to the mandibular pogonion to determine reconstructive accuracy. Inter-rater reliability was assessed via intraclass correlation coefficient. Demographic, clinical, surgical, and radiographic variables were also collected to profile cohort characteristics and outcomes. Results After exclusions due to poor or no post-operative imaging, 25 patients were included in the final analysis. Squamous cell carcinoma ( n  = 19) was the most common pathology, and males ( n  = 18) were represented more than females ( n  = 7). 96% (24/25) of patients had good plate adaptation and 96% (24/25) had good osteotomy adaptation. Reconstruction accuracy measured by comparing preoperative to postoperative anatomic alignment was very good, with an average absolute difference across all patients of only 3.10 mm. Inter-rater reliability between measurements was high with an average 0.98 intraclass correlation coefficient. Conclusions We present a novel method for measuring mandibular reconstruction accuracy through the use of the maxilla as the anatomic landmark. Furthermore, our profile of patients who underwent segmental mandibulectomy and reconstruction with the assistance of in-house produced 3D printed patient-specific models appears to result in suitable anatomic alignment of the reconstructed mandible and produce good clinical outcomes.

Objective Early and integrated palliative care (PC) interventions are recommended for advanced‐stage cancers. The rate with which patients with stage IV oral cavity squamous cell carcinoma (OCSCC) receive PC as part of their oncologic care is unknown. We sought to understand the utilization of PC for patients with stage IV OCSCC in Medicaid expanded versus non‐expanded states. Study Design Retrospective cohort. Setting National Cancer Database was queried for patients with stage IV OCSCC from 2004 to 2017. Methods Patients in Medicaid expanded (EXP) states were categorized as pre‐expansion (pre‐EXP) or post‐expansion (post‐EXP). Patients in nonexpanded states (NEXP) were categorized as diagnosed before 2014 (pre‐NEXP) or during/after 2014 (post‐NEXP). Multivariable logistic regressions were used to compare receipt of PC among pre‐EXP and post‐EXP patients, and separately among post‐EXP and post‐NEXP cases. Results Among 15,356 patients who met inclusion criteria, 629 (4.10%) received PC. There was a trend towards increased receipt of PC in post‐EXP compared to pre‐EXP cases, but this did not reach statistical significance. Among pre‐EXP and post‐EXP cases, patients were more likely to receive PC with the lowest income quartile, tongue cancer as the oral cavity subsite, and no insurance. Conclusion There was no significant difference of PC receipt for patients with stage IV OCSCC in Medicaid expanded versus non‐expanded states. Results among patients in pre‐EXP and post‐EXP states suggest increased PC use among more disadvantaged patient groups. Further analysis on receipt of PC in vulnerable patient populations with advanced‐stage cancer is warranted.