Papillomavirus-positive Oropharyngeal Squamous Cell Carcinoma Research Articles

Automated AJCC Restaging for Oropharyngeal Cancer Research.

With the American Joint Committee on Cancer (AJCC) 8th edition staging guidelines update, human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is now staged separately from its HPV-negative counterpart, preventing meaningful comparison of cases staged with the 7th versus 8th edition criteria. Manual restaging is time-consuming and error-prone, hindering multiyear analyses for HPV+ OPSCC. We developed an automated computational tool for re-classifying HPV+ OPSCC pathological and clinical tumor staging from AJCC 7th to 8th edition. The tool is designed to handle large data sets, ensuring comprehensive and accurate analysis of historic HPV+ OPSCC data. Validated against institutional and National Cancer Database data sets, the algorithm achieved accuracies of 100% (95% confidence interval [CI]98.8%-100%) and 93.4% (95% CI93.1%-93.7%), successfully restaging 326/326 and 26,505/28,374 cases, respectively. With its open-source design, this computational tool can enhance future HPV+ OPSCC research and inspire similar tools for other cancer types and subsequent AJCC editions.

Cost-Effectiveness Analysis of PET-CT Surveillance After Treatment of Human Papillomavirus-Positive Oropharyngeal Cancer.

To determine the cost-effectiveness of surveillance imaging with PET/CT scan among patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma. Cost-effectiveness analysis. Oncologic care centers in the United States with head and neck oncologic surgeons and physicians. We compared the cost-effectiveness of 2 posttreatment surveillance strategies: clinical surveillance with the addition of PET/CT scan versus clinical surveillance alone in human papillomavirus-positive oropharyngeal squamous cell carcinoma patients. We constructed a Markov decision model which was analyzed from a third-party payer's perspective using 1-year Markov cycles and a 30-year time horizon. Values for transition probabilities, costs, health care utilities, and their studied ranges were derived from the literature. The incremental cost-effectiveness ratio for PET/CT with clinical surveillance versus clinical surveillance alone was $89,850 per quality-adjusted life year gained. Flexible fiberoptic scope exams during clinical surveillance would have to be over 51% sensitive or PET/CT scan cost would have to exceed $1678 for clinical surveillance alone to be more cost-effective. The willingness-to-pay threshold at which imaging surveillance was equally cost-effective to clinical surveillance was approximately $80,000/QALY. Despite lower recurrence rates of human papillomavirus-positive oropharyngeal cancer, a single PET/CT scan within 6 months after primary treatment remains a cost-effective tool for routine surveillance when its cost does not exceed $1678. The cost-effectiveness of this strategy is also dependent on the clinical surveillance sensitivity (flexible fiberoptic pharyngoscopy), and willingness-to-pay thresholds which vary by country.

Surgical margin status and role of adjuvant therapy in human papillomavirus-positive oropharyngeal cancer.

We analyzed the difference in treatment results according to safety margin range and studied the role of adjuvant therapy in patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). A total of 279 patients with HPV+ OPSCC were included in this study. Surgical margin and T classification were significant prognostic factors related to death. The difference in locoregional recurrence was analyzed by dividing the safety margin into groups of <1, 1-5, and >5 mm. There was no significant difference in local-regional recurrence for T1-T2 lesions between the three groups. Adjuvant therapy can significantly reduce disease recurrence in HPV+ OPSCC patients with risk factors. In T1-T2 lesions without other risk factors, even with a safety margin ≥1 mm, adjuvant therapy can potentially be omitted. Adjuvant therapy can significantly reduce disease recurrence in HPV+ OPSCC patients with risk factors.

Oropharyngeal Carcinoma with a Special Focus on HPV-Related Squamous Cell Carcinoma

Human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system separates HPV-OPSCC from its HPV-negative counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment deintensification as a means to improve quality of life while maintaining acceptable survival outcomes. Owing to the distinct biology of HPV-OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage, highlighting the need for diagnostic biomarkers to aid in earlier detection. In this review, we highlight important advances in the epidemiology, pathology, diagnosis, and clinical management of HPV-OPSCC and underscore the need for a progressive understanding of the molecular basis of this disease toward early detection and precision care.

Predictive Value of 18F-Fluorodeoxyglucose Positron-Emission Tomography Metabolic and Volumetric Parameters for Systemic Metastasis in Tonsillar Cancer.

Although the prognosis of tonsillar cancer (human papillomavirus-positive oropharyngeal squamous cell carcinoma) is improving, disease control failure (distant metastasis) still occurs in some cases. We explored whether several 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) parameters can predict metastasis. We retrospectively reviewed the medical records of 55 patients with tonsil squamous cell carcinoma who underwent pretreatment 18F-FDG positron-emission tomography/computed tomography (PET/CT) followed by primary surgery. During the follow-up period, systemic metastases were found in 7 of the 55 patients. The most common sites were the lungs (33%), bone (22%), brain/skull base (22%), small bowel (11%), and liver (11%). Pathologically, P53 mutation was less common in patients with systemic metastasis (41.7% vs. 14.3%, p = 0.054) than without systemic metastasis. In terms of PET parameters, the metabolic tumor volume (MTV2.5) and total lesion glycolysis (TLG2.5) values were lower in the primary tumor, and higher in the metastatic lymph nodes, of human papillomavirus (HPV)-positive compared to HPV-negative patients (all p &lt; 0.05). The MTV2.5, TLG2.5, and tumor-to-liver uptake ratio were 36.07 ± 54.24 cm3, 183.46 ± 298.62, and 4.90 ± 2.77, respectively, in the systemic metastasis group, respectively; all of these values were higher than those of the patients without systemic metastasis (all p &lt; 0.05). The MTV2.5 value was significantly different between the groups even when the values for the primary tumor and metastatic lymph nodes were summed (53.53 ± 57.78 cm3, p = 0.036). The cut-off value, area under the curve (95% confidence interval), sensitivity, and specificity of MTV2.5 for predicting systemic metastasis were 11.250 cm3, 0.584 (0.036-0.832), 0.571, and 0.565, respectively. The MTV2.5 of metastatic lymph nodes and summed MTV2.5 values of the primary tumor and metastatic lymph nodes were significantly higher in tonsillar cancer patients with than without systemic metastases. We suggest PET/CT scanning for pre-treatment cancer work-up and post-treatment surveillance to consider additional systemic therapy in patients with a high risk of disease control failure.

Association of Intraoperative Frozen Section Controls With Improved Margin Assessment During Transoral Robotic Surgery for Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma

Intraoperative margin assessment is an important technique for ensuring complete tumor resection in malignant cancers. However, in patients undergoing transoral robotic surgery (TORS) for oropharyngeal carcinomas, tissue artifact may provide pathologic uncertainty. To assess the benefit of providing frozen section control samples ("positive tumor biopsies") for use during intraoperative margin assessment for patients undergoing TORS for human papillomavirus (HPV)-16-positive oropharyngeal squamous cell carcinoma (OPSCC). In this cohort study, patients receiving curative-intent TORS for biopsy-proven HPV-16-positive OPSCC performed by a single attending surgeon (A.H.M.) at Ronald Reagan UCLA Medical Center from 2017 to 2021 were included in a retrospective data analysis. Exclusion criteria included HPV-negative status, participation in clinical trials, and tumors of unknown primary origin. Survival outcomes investigated included overall and disease-free survival. Adverse pathologic outcomes measured included occurrence of nondiagnostic margins and margin reversal from frozen to fixed pathology. Of the 170 patients included (mean [SD] age, 61.8 [9.9] years; 140 [82%] male), 50% of patients (n = 85) received a frozen section control. Use of a frozen section control was associated with statistically significantly improved sensitivity of intraoperative margin assessment, from 82.8% to 88.9% (difference, 6.1%; 95% CI, 3.9%-8.3%). Eleven percent (n = 18) of all tumors evaluated exhibited at least 1 nondiagnostic intraoperative margin, and 11% (n = 18) experienced margin reversal from frozen to fixed pathology. In patients with nondiagnostic margins, use of frozen section controls was associated with statistically significantly reduced time spent in the operating room (Cohen d, 1.14; 95% CI, 0.12-2.14). In this cohort study, frozen intraoperative margins assessed during TORS resections of HPV-16-positive OPSCC were diagnostically challenging. Adverse pathologic outcomes, such as margin status reversal from positive on frozen pathology to negative on formal analysis, were common. Providing intraoperative frozen section control biopsies may offer clarity in cases with nondiagnostic margins, reducing the need for additional sampling and time spent in the operating room.

Adjuvant radiation vs Chemoradiation in HPV+ oropharyngeal squamous cell carcinoma with extranodal extension

A survival benefit from adjuvant chemoradiotherapy (CRT) over radiotherapy (RT) in treatment of surgically resected Human Papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) with extranodal extension (ENE) remains unclear. The National Cancer Database was queried for cases of surgically resected to negative margins HPV + OPSCC from 2010-2015. Demographics, tumor factors, and treatment data were obtained. Survival rates, hazard ratios (HR), and odds ratios were obtained. Propensity score matching was conducted. 4971 patients met inclusion criteria. 60.7% received adjuvant CRT; 41.1% of cases were ENE+. ENE (HR: 2.28) increased risk of death. In ENE + cases, there was no difference in survival between CRT and RT cohorts following propensity score matching ( P = 0.231). The use of adjuvant CRT declined over the study period ( P < .001) while ENE status remained the same ( P = 0.229). The presence of ENE is a negative prognostic feature in HPV + OPSCC. However, the use of CRT over RT did not impart a survival benefit in patients with ENE + HPV + OPSCC surgically resected to negative margins. 4. • 1 – ENE was strongly predictive of receiving adjuvant CRT over RT alone. • 2 – Patients who had ENE had modestly worse survival compared to patients without ENE. • 3 – In patients with ENE, adjuvant CRT did not confer a survival benefit over adjuvant RT alone.

The Prevalence of Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma at One of the Largest Tertiary Care Centers in Sub-Saharan Africa.

Limited data exist on the prevalence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma in sub-Saharan Africa. To determine the prevalence of HPV-positive oropharyngeal squamous cell carcinoma at a large tertiary care center in South Africa. A total of 266 oropharyngeal squamous cell carcinomas diagnosed during an 11-year period (2007-2017) were selected for evaluation. Cases staining positive for p16 immunohistochemistry were evaluated for high-risk HPV using the BD Onclarity assay (BD Diagnostics, Sparks, Maryland). Of 266 oropharyngeal squamous cell carcinomas, 14% (n = 36) were positive for p16. Polymerase chain reaction for high-risk HPV performed on the p16-positive cases was negative in 23 cases and positive in 13 cases (13 of 266; 5%). p16 showed a positive predictive value of 36.1%. The HPV subtypes were HPV-16 (n = 10), HPV-18 (n = 1), HPV-52 (n = 1), and HPV-31 (n = 1). Human papillomavirus-positive cases occurred in 10 men and 3 women (mean age, 51 years) and arose from the tonsil (n = 10) or base of the tongue (n = 3). The HPV-positive cases were non-keratinizing (n = 10) or partially keratinizing (n = 1). Partially/nonkeratinizing cases revealed a modest improvement in p16 positive predictive value (11 of 21; 52.4%). The presence of high-risk HPV in 5% of cases suggests that high-risk HPV is a minor etiologic agent in oropharyngeal squamous cell carcinoma in this region. Given its suboptimal positive predictive value, p16 is not a reliable marker for high-risk HPV infection in this region. When p16 is positive, HPV-specific testing is necessary. The identification of less common high-risk HPV types, HPV-52 and HPV-31, may influence current local vaccination strategies.

Abstract 5241: Differences in PD-L1 expression by smoking status in HPV positive oropharyngeal cancer

Abstract Introduction: As the incidence of human papillomavirus-positive (HPV +) oropharyngeal squamous cell carcinoma (OPSCC) continues to increase, it is important to optimize treatment regimens. There is growing evidence demonstrating the efficacy and safety of anti-PD-1 immunotherapy, either as monotherapy or in combination with chemotherapy, for patients with programmed death-ligand 1 (PD-L1) positive head and neck squamous cell carcinoma. Greater PD-L1 expression has been associated with greater treatment response and improved overall survival independent of treatment modality. Prior studies have observed increased PD-L1 expression and improved treatment response in HPV(+) as compared to HPV(-) tumors. In contrast, HPV(-) disease, in which smoking is causative in most cases, is typically associated with unfavorable outcomes and lower rates of PD-L1 expression. In the present study, we sought to explore the effects of smoking on PD-L1 expression in HPV(+) tumors based on smoking status. We hypothesized that smokers would demonstrate lower levels of PD-L1 expression as compared to non-smokers. Methods: Using an existing tissue bank, we identified a cohort of 52 HPV(+) tumors from patients with available smoking data. A tissue microarray was constructed with cores taken from the paraffin embedded tumor blocks. A single 0.5 micron slide was created and we examined PDL-1 expression by immunohistochemistry in 47 intact cores. Visiopharm software was used for quantitative analysis of area stained per total cellular area (Figure 2). Mann-Whitney U test was then performed to compare PD-L1 expression between current smokers and former/never smokers (Figure 1). Forty-four of the patients in the cohort had RNA-based Nanostring immuno-oncology assay data available. We were able to obtain paired quantitative IHC and Nanostring based PD-L1 (CD274) gene expression values for 40 patients and Spearman's correlation was performed (Figure 3). Results: The primary tumor site was tonsil in 29 (56%) patients, 22 (42%) base of tongue, and 1 (2%) soft palate. Females made up 10% of the cohort. There were 9 (17%) current smokers, 20 (38%) former, and 23 (44%) never smokers. Pack-years was available for 22 (76%) of the current and former smokers (median: 30, range: 1-75 pack years). There were 5 patient deaths, and 10 patients experienced recurrence. PD-L1 expression on IHC was not predictive of death or recurrence (p=0.39 and p=0.07, respectively). Median follow up time was 20.5 months (range: 2.7 to 83 months). There was a significant difference in PD-L1 expression on IHC between current smokers and the former/never group (Figure 1). Relative gene expression of CD274 measured by the Nanostring assay was lower in current smokers as compared to former/never smokers, however this trend did not meet significance. There was a strong positive linear correlation between Nanostring based CD274 gene expression and PD-L1 expression on IHC (r=0.68, p &amp;lt 0.0001). Conclusion: Current smoking status at the time of diagnosis is associated with decreased PD-L1 expression as compared to former and never smokers. These results may have implications when considering immune checkpoint inhibition therapy in smokers with HPV(+) OPSCC. Citation Format: Ricardo J. Ramirez, Benjamin Wahle, Zixing Liu, Angela Mazul, Paul Zolkind, Mena Mansour, Krzysztof Hyrc, Jose P. Zevallos. Differences in PD-L1 expression by smoking status in HPV positive oropharyngeal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5241.

Pretreatment DWI with Histogram Analysis of the ADC in Predicting the Outcome of Advanced Oropharyngeal Cancer with Known Human Papillomavirus Status Treated with Chemoradiation.

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in the period from the 1970s to 2004, due to increase of infection with human papilloma virus (HPV). This study aimed to examine the role of histogram analysis of the ADC in treatment response and survival prediction of patients with oropharyngeal squamous cell carcinoma and known human papillomavirus status. This was a retrospective single-center study. Following inclusion and exclusion criteria, data for 59 patients affected by T2-T4 (according to the 8th edition of the AJCC Cancer Staging Manual) oropharyngeal squamous cell carcinoma were retrieved. Twenty-eight had human papillomavirus-positive oropharyngeal squamous cell carcinoma, while 31 had human papillomavirus-negative oropharyngeal squamous cell carcinoma. All patients underwent a pretreatment MR imaging. Histogram analysis of ADC maps obtained by DWI (b = 0-1000 mm/s2) was performed on the central section of all of tumors. The minimum follow-up period was 2 years. Histogram ADC parameters were associated with progression-free survival and overall survival. Univariable and multivariable Cox models were applied to the data; P values were corrected using the Benjamini-Hochberg method. At univariable analysis, both human papillomavirus status and mean ADC were associated with progression-free survival (hazard ratio = 0.267, P < .05, and hazard ratio = 1.0028, P ≤ .05, respectively), while only human papillomavirus status was associated with overall survival (hazard ratio = 0.213, P ≤ .05) before correction. At multivariable analysis, no parameter was included (in fact, human papillomavirus status lost significance after correction). If we separated the patients into 2 subgroups according to human papillomavirus status, ADC entropy was associated with overall survival in the human papillomavirus-negative group (hazard ratio = 4.846, P = .01). ADC and human papillomavirus status are related to progression-free survival in patients treated with chemoradiation for advanced oropharyngeal squamous cell carcinoma; however, this association seems to result from the strong association between ADC and human papillomavirus status.

Estrogen receptor \u03b1 as a predictive biomarker for survival in human papillomavirus-positive oropharyngeal squamous cell carcinoma

BackgroundAlthough oropharyngeal squamous cell carcinoma (OPSCC) with human papillomavirus (HPV) infection has a good prognosis, the accurate prediction of survival and risk of treatment failure is essential to design deintensification regimens. Here, we investigated estrogen receptor α (ERα) as a prognostic biomarker with therapeutic implications in OPSCC alongside factors associated with HPV infection.MethodsWe performed immunohistochemistry for ERα and p53 using formalin-fixed, paraffin-embedded tissues and assessed the HPV status using p16 immunohistochemistry and HPV DNA testing in 113 consecutive patients with OPSCC treated with surgical resection or radiotherapy/chemoradiotherapy.ResultsERα expression and p53 alteration was observed in 35.4% and 21.2% OPSCCs; 45.6% and 1.3% p16+/HPV+ OPSCCs; and 11.5% and 76.9% p16− OPSCCs, respectively. These data suggest that OPSCC pathogenesis varies with HPV status. Furthermore, ERα expression was associated with improved overall survival (OS) in both HPV+ (p16+/HPV+ OPSCC) and p16+ (p16+ OPSCC irrespective of HPV status) models (p = 0.005 and p = 0.006, respectively) and with improved OS adjusted for stage (p = 0.037, hazard ratio: 0.109, 95% confidence interval 0.013–0.871) in the p16+ model.ConclusionsERα is a potential predictive biomarker for improved survival in both HPV+ and p16+ OPSCC models.

Determination of high-risk HPV status of head and neck squamous cell carcinoma using the Roche cobas HPV test on cytologic specimens and acellular supernatant fluid.

High-risk human papillomavirus-positive (hrHPV+) oropharyngeal squamous cell carcinomas comprise a subset of head and neck squamous cell carcinomas (HNSCCs) with a distinct biology and prognosis. Commonly, the diagnosis of HNSCC is rendered on fine-needle aspiration (FNA). Because cell blocks may be insufficient for determining HPV status using microscopy-based techniques, the ability of liquid-based assays was examined in the current study. The performance of the Roche cobas 4800 platform was evaluated on the FNA material from the cell pellet and corresponding cell-free supernatant fluid specimens of primary and metastatic HNSCCs. These results were compared with the p16 immunostain result from the histologic material obtained from the same patient. Discrepant cases were adjudicated using hrHPV RNA in situ hybridization. A total of 41 samples (23 primary tumors and 18 lymph node metastases) were acquired from 34 patients with HNSCC. Primary tumors included the oropharynx (20 samples), oral cavity (13 samples), larynx (3 samples), and skin (3 samples). In 2 cases, a primary tumor could not be identified. Twenty-three samples (56%) were found to be p16 positive by immunohistochemistry. Twenty-two samples were found to be positive on cobas hrHPV testing from both cell pellet and cell-free supernatant fluid. Two cell-free supernatant fluid specimens yielded indeterminate cobas results. At the time additional hrHPV RNA in situ hybridization analysis was performed, one cobas-positive cell pellet was deemed to be a false-positive result. The sensitivity of the cobas assay was 100% for pellet material and cell-free supernatant fluid, with specificities of 94.7% and 100%, respectively. cobas hrHPV testing of HNSCC specimens demonstrated high concordance with p16 immunohistochemistry on the corresponding cell block and/or tissue specimen. Using the cell-free supernatant fluid in this platform could provide accurate HPV results while conserving material for cytomorphologic analyses.

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

BackgroundPatients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches.MethodsThis is a multicenter phase II study randomizing one hundred and forty patients with T1–2 N0–2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50–60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity.DiscussionThis study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials.Trial RegistrationClinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Infiltrates of M2-Like Tumour-Associated Macrophages Are Adverse Prognostic Factor in Patients with Human Papillomavirus-Negative but Not in Human Papillomavirus-Positive Oropharyngeal Squamous Cell Carcinoma

Introduction: Human papillomavirus with a high oncogenic potential (HR-HPV) is responsible for more than a half of squamous cell carcinomas of the oropharynx. The HR-HPV-dependent cases of this tumour have a better prognosis compared to the HR-HPV-negative cases, despite the usually more advanced disease at the time of diagnosis. In addition to genetic and epigenetic factors, the causes of this more favourable course of the disease are also seen in the participation of the tumour microenvironment, including the patient’s immune system. Macrophages are one of the most important elements of the immunocompetent cells landscape that make up the tumour microenvironment. Traditionally, they are divided into 2 groups: inflammatory macrophages with the M1 phenotype and tumour-associated macrophages known as M2 phenotype macrophages. Objective: The aim of this study was to investigate the impact of the macrophage infiltrates intensity of the M1/M2 and M2 phenotype separately on the clinical outcome of patients with squamous cell carcinoma of the oropharynx (OPSCC), taking into account the HR-HPV status of tumours. Methods: The study involved 85 patients with OPSCC in which HR-HPV status in tumour tissue was determined using a double-check algorithm including the detection of viral DNA by RT-PCR method with subsequent confirmation of its biological activity by immunohistochemical demonstrating the P16^INK4A protein overexpression. In each of the groups formed on the basis of HR-HPV status, macrophages were discriminated using CD68 and CD163 proteins as markers of pan-macrophage and M2 phenotype. The intensity of infiltrates was quantified by means of computer-assisted analysis in digital images of whole slides (virtual slides) separately in tumour tissue and stroma. Results: In HPV-positive patients, significantly more intense infiltration of both M1/M2 and M2 macrophages was found in the tumour stroma compared to HPV-negative patients. The infiltrates from both types of macrophages in the tumour tissue were less intense and did not differ between these groups. Intensive infiltration of CD68⁺ macrophages in the tumour front was associated with higher rate of nodal failures and a shorter nodal control in both HR-HPV groups. In the group of HR-HPV-negative patients, heavy infiltration of CD163⁺ macrophages was associated with significantly shorter: loco-regional control (LRC), metastasis-free survival and overall survival (OS). These parameters and prognosis in patients with scanty CD163⁺ infiltration were similar to favourable outcomes in HR-HPV-positive patients. The relative risk of local-regional recurrence, distant metastases and disease-related death in HR-HPV-negative patients with intense CD163⁺ infiltrates was, respectively, 4.7, 5.4 and 5.7 compared to patients with scanty infiltrates. Conclusions: Tumours with a positive HR-HPV status demonstrate intense infiltrations of total pool M1/M2 and M2 macrophages. In the group of HPV-negative patients, intensive M1/M2 macrophage infiltrates correlate with higher risk of nodal failures, and intensive M2 infiltrates are an adverse prognostic factor for LRC, metastasis-free survival and OS.

National treatment trends in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC) is associated with dramatically improved survival in comparison with HPV-negative OPC and can be successfully treated with surgical and nonsurgical approaches. National treatment trends for OPC were investigated with the National Cancer Data Base (NCDB). The NCDB was reviewed for primary HPV-mediated OPC in 2010-2014. Multivariable regression was used to identify predictors of both nonsurgical therapy and receipt of adjuvant chemoradiation (CRT). There were 13,363 patients identified with a median age at diagnosis of 58years. The incidence of triple-modality treatment (surgery with adjuvant chemotherapy) decreased from 23.7% in 2010 to 16.9% in 2014 (R2 =0.96), whereas the incidence of nonsurgical treatment increased from 63.9% to 68.7% (R2 =0.89). Hospitals in the top treatment volume quartile (quartile 1 [Q1]; n=29) had a lower rate of positive margins (16.3%) than bottom-quartile centers (n=741; rate of positive margins, 36.4%; P<.001); Q1 hospitals used surgical therapy significantly more. Independent predictors of nonsurgical therapy included older age, advanced disease, lower hospital volume, and living closer to the hospital or outside the Pacific United States. In surgically treated patients, younger age, lower hospital volume, nodal disease, positive surgical margins, and extranodal extension (ENE) also predicted more adjuvant CRT use. The use of upfront surgical treatment decreased from 2010 to 2014. Hospital volume shows a strong, inverse correlation with the rate of positive surgical margins. The upfront treatment strategy is predicted not only by staging but also by patient-, geographic-, and hospital-specific factors. Lower hospital volume remains independently associated with increased triple-modality therapy after adjustments for positive margins, ENE, and pathologic staging.

Human papillomavirus–positive oropharyngeal squamous cell carcinoma manifesting as glossopharyngeal neuralgia

Human papillomavirus–positive oropharyngeal squamous cell carcinoma manifesting as glossopharyngeal neuralgia

Impact of cisplatin dose and smoking pack-years in human papillomavirus–positive oropharyngeal squamous cell carcinoma treated with chemoradiotherapy

BackgroundTo evaluate the impact of cisplatin cumulative dose (CDDP-D) and smoking pack-years (PYs) on cause-specific survival (CSS) and overall survival (OS) in human papillomavirus–positive (HPV+) oropharyngeal carcinoma (OPSCC) using the eighth edition tumour-node-metastasis (TNM) staging classification (TNM8). Patients and methodsWe reviewed patients with HPV+ OPSCC treated with high-dose CDDP and intensity-modulated radiotherapy between 2005 and 2015 at Princess Margaret Cancer Centre. CSS and OS were compared according to CDDP-D <200/=200/>200 mg/m2 stratified by TNM8. ResultsA total of 482 consecutive patients were evaluated (stage I/II/III: N = 189/174/119; CDDP-D <200/=200/>200 mg/m2: N = 112/220/150). Median follow-up duration was 5.1 years (range: 0.6–12.8). Five-year CSS and OS differed by stages I/II/III: 96%/85%/88% (p=0.005) and 93%/84%/78% (p = 0.001), respectively. Five-year CSS by CDDP-D <200/=200/>200 mg/m2 was similar in stage I (98%/95%/95%, p = 0.74) and stage II (88%/84%/84%, p = 0.86) but different in stage III (76%/98%/84%, p = 0.02). Five-year OS by CDDP-D <200/=200/>200 mg/m2 did not differ significantly among stages. In the multivariable analysis, CDDP-D <200 mg/m2 did not influence CSS in the whole cohort versus = 200/>200 mg/m2 (p=0.53/0.79, respectively) but was associated with reduced CSS in stage III subgroup versus =200 mg/m2 (=200 mg/m2 versus < 200 mg/m2 hazard ratio [HR] = 0.08; 95% confidence interval [CI]: 0.01–0.67; p = 0.02). Higher smoking PYs had no effect on CSS (p = 0.34) but reduced OS in the whole cohort (HR = 1.14 [95% CI: 1.02–1.27], p=0.01). ConclusionCDDP-D correlated with neither survival nor disease-specific outcomes in this large and homogeneous HPV+ cohort, although reduced CSS was observed in stageIII HPV+ OPSCC receiving CDDP-D <200 mg/m2. Smoking PYs were negatively associated with OS but not with CSS.

Extranodal extension is a strong prognosticator in HPV-positive oropharyngeal squamous cell carcinoma.

To comprehensively examine the prognostic significance of extranodal extension (ENE) in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC). Retrospective cohort of cases diagnosed with HPV-positive OPSCC from 2010 to 2015 in the National Cancer Database. Inclusion of all OPSCC HPV-positive cases with appropriate International Classification of Diseases-0-3 codes that received surgery with a neck dissection. Univariate and multivariable analyses were conducted. Hazard ratios (HR) for the independent effects of ENE and N stage on overall survival were estimated by Cox proportional hazards regression. Cases that were ENE-negative had the highest 5-year survival (92.6%; 95% confidence interval [CI]: 90.5%-94.7%). ENE-positive cases had the lowest 5-year survival (84.0%; 95% CI: 80.7%-87.4%). After adjusting for confounding variables, ENE-positivity was associated with almost twice the hazard of death (HR = 1.90; 95% CI: 1.35-2.67) compared to ENE-negative cases. Nodal (N) category 1, ENE-positive status was associated with an increased risk of death (HR = 1.88; 95% CI: 1.26-2.80) compared with N1, ENE-negative status. Compared to N1/ENE-negative cases, N2/ENE-positive cases had the poorest survival (HR: 2.93; 95% CI: 1.94-4.43). Both microscopic and macroscopic ENE were associated with worse outcomes compared to node-positive/ENE-negative status. The implementation of the American Joint Committee on Cancer 8th edition staging system provides a much-improved framework to develop and discuss treatment plans for HPV-positive OPSCC. We feel that careful consideration should be given to the importance of ENE in patients with HPV-positive OPSCC. 4 Laryngoscope, 130:939-945, 2020.

Tumor-infiltrating lymphocyte quantification stratifies early-stage human papillomavirus oropharynx cancer prognosis.

To evaluate if a simple method for assessing tumor-infiltrating lymphocytes (TIL) in primary tumor specimens improves the prognostic value of the American Joint Committee on Cancer, 8th Edition (AJCC8) cancer staging system in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-OPC). Retrospective study. In this study, TIL density was quantified on hematoxylin and eosin (H&E)-stained specimens from patients presenting to Johns Hopkins Hospital between 2009 and 2017 who underwent primary surgical therapy and had primary tumor specimens available for analysis. The prognostic effect of TIL density was evaluated by Kaplan-Meier method and Cox proportional hazards models considering recurrence-free survival (RFS) as the primary outcome. This study included 132 patients. Ninety-five percent were classified by clinical criteria with AJCC8 early-stage disease (stage I: 82%, stage II: 13%). After 84 months of follow-up, 15 recurrences were observed. Among clinically early-stage disease, TILhigh status was associated with improved RFS compared to TILlow (P = .002). Adjusted analysis showed TILhigh status was associated with 79% lower risk of recurrence than TILlow (adjusted hazard ratio [aHR]: 0.210, 95% confidence interval [CI]: 0.061-0.723). In clinical stage I disease, TILhigh status was associated with improved RFS compared to TILlow in both univariate and multivariate analyses (hazard ratio: 0.235, P = .021; aHR: 0.218; 95% CI: 0.058-0.822). TIL density similarly stratified risk in pathologically staged disease. In patients with AJCC8 stage I disease, low TIL density was associated with diminished RFS. Our data suggest that assessing TIL density on H&E-stained primary tumor specimens may enhance the prognostic resolution of the AJCC8 staging criteria for HPV-OPC. 4 Laryngoscope, 130:930-938, 2020.

From presumed benign neck masses to delayed recognition of human papillomavirus-positive oropharyngeal cancer.

To describe patients with delayed diagnosis of human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-OPC) after initial incorrect diagnosis of branchial cleft cyst or nondiagnostic workup of unilateral neck mass. Retrospective case series. Patients with delayed diagnosis of HPV-OPC after initial nondiagnostic workup for unilateral neck mass were eligible. Medical record abstraction was performed to describe clinical characteristics at initial presentation and later diagnosis of HPV-OPC. To estimate nodal growth rates, the short axis diameter of the lymph nodes was determined from imaging reports. Six patients met eligibility criteria. After a median interval of 42 months (range, 3 months-7 years) from initial presentation with unilateral neck mass, patients were diagnosed with HPV-OPC. At the time of HPV-OPC diagnosis, five were AJCC eighth edition overall stage I, and one was stage II. Primary tumors were T0 or T1 in the majority (83.3%, n = 5). Among five patients with available serial imaging, despite diagnostic delay, three of five still had a single lymph node without involvement of additional nodes, whereas the remaining two developed additional suspicious nodes (ipsilateral and contralateral). Two of five developed evidence of extranodal extension. Median lymph node growth was 9.5% per year (range, -6% to 32%). Although the natural history of HPV-OPC is not well understood, this case series suggests that it can be slow growing and mimic benign processes, leading to diagnostic delays. Adults presenting with neck masses should undergo complete diagnostic evaluation. 4 Laryngoscope, 130:392-397, 2020.