Substantial molecular evidence suggests a role for human papillomavirus (HPV) in the pathogenesis of oropharyngeal squamous-cell carcinoma, but epidemiologic data have been inconsistent.
We performed ...a hospital-based, case-control study of 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer. Multivariate logistic-regression models were used for case-control comparisons.
A high lifetime number of vaginal-sex partners (26 or more) was associated with oropharyngeal cancer (odds ratio, 3.1; 95% confidence interval CI, 1.5 to 6.5), as was a high lifetime number of oral-sex partners (6 or more) (odds ratio, 3.4; 95% CI, 1.3 to 8.8). The degree of association increased with the number of vaginal-sex and oral-sex partners (P values for trend, 0.002 and 0.009, respectively). Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infection with any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to 26.4), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detected in 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens, and 64% of patients with cancer were seropositive for the HPV-16 oncoprotein E6, E7, or both. HPV-16 L1 seropositivity was highly associated with oropharyngeal cancer among subjects with a history of heavy tobacco and alcohol use (odds ratio, 19.4; 95% CI, 3.3 to 113.9) and among those without such a history (odds ratio, 33.6; 95% CI, 13.3 to 84.8). The association was similarly increased among subjects with oral HPV-16 infection, regardless of their tobacco and alcohol use. By contrast, tobacco and alcohol use increased the association with oropharyngeal cancer primarily among subjects without exposure to HPV-16.
Oral HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use.
This review examines the general cellular and molecular underpinnings of human papillomavirus (HPV)-related carcinogenesis in the context of head and neck squamous cell carcinoma (HNSCC) and focuses ...on HPV-positive oropharyngeal squamous cell carcinoma in areas for which specific data is available. It covers the major pathways dysregulated in HPV-positive HNSCC and the genome-wide changes associated with this disease.
HPV-positive oropharyngeal squamous cell carcinoma (HPV-OSCC) is associated with oral sexual behaviors. The sharp rise in incidence of HPV-OSCC in the USA has been attributed to changes in sexual ...norms over the past five decades, with lower age at sexual debut and higher numbers of sexual partners per individual. In addition, variations in HPV-OSCC prevalence by race, age cohort and gender may be attributable to differences in oral sexual behaviors among these groups. Oral HPV infection is the putative precursor to HPV-OSCC. Risk factors for oral HPV incidence, prevalence, clearance and persistence are crucial to understanding how, and in whom, oral HPV infection progresses to malignancy. Future investigation should focus on elucidating the natural history of oral HPV infection persistence and malignant transformation, developing effective screening tools and exploring opportunities for prevention such as vaccination and public health education.
The presence of human papillomavirus (HPV) in unknown primary squamous cell carcinoma (UPSCC) of the head and neck at initial presentation focuses the investigation for the primary tumor on the ...oropharynx. The trends, frequency, and detection rate of UPSCCs have not been evaluated in the context of HPV tumor status.
To determine the frequency of UPSCC over time and to evaluate the proportion of HPV-positive UPSCCs.
Retrospective, single-institutional case series of patients diagnosed with UPSCC and evaluated at the Johns Hopkins Hospital from January 1, 2005, to June 1, 2014. Human papillomavirus tumor status was determined by p16 immunohistochemical analysis and/or high-risk HPV DNA by in situ hybridization as clinically available.
Number and clinical characteristics of UPSCC cases over time.
Eighty-four UPSCC cases were eligible for analysis. The mean age of the patients was 57.3 years (range 29-80 years), and 88.1% (n = 74) were male. The frequency of UPSCC increased significantly over time (P for trend = .01) and was significantly higher during later calendar periods (14 cases during 2005-2008 vs 39 cases during 2012-2014, P = .03). A total of 69 cases (90.7%) with available HPV tumor status were HPV-positive. The patients with HPV-positive UPSCC were significantly more likely to be male (91% vs 42.9%, P = .005) and younger (56.1 vs 67.7 years, P = .002) than the HPV-negative patients with UPSCC. The overall primary tumor site detection rate was 59.3% (n = 48). There was a nonsignificant increase in the detection rate from calendar periods 2005-2008 to 2012-2014 (50.0% vs 64.9%, P = .38). Since transoral robotic surgery was adopted in the diagnostic evaluation of UPSCC in 2011, a nonsignificant increase in the detection of primary tumors was observed (53.8% vs 64.3%, P = .34).
The frequency of UPSCC has increased significantly in recent calendar periods, and most cases are HPV-positive. As expected, patients with HPV-positive UPSCC tend to be male and younger.
Background
Radiation Therapy Oncology Group (RTOG)‐0129 recursive partitioning analysis was the basis for risk‐based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors’ ...knowledge, the question of whether RTOG‐0129 overall survival (OS) estimates for low‐risk, intermediate‐risk, and high‐risk groups are similar in other data sets or applicable to progression‐free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG‐0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups.
Methods
Prospective randomized clinical trials were analyzed retrospectively. RTOG‐0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG‐0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible.
Results
There was a total of 260 patients and 287 patients, respectively, from RTOG‐0129 and RTOG‐0522, with median follow‐ups for surviving patients of 7.9 years (range, 1.7‐9.9 years) and 4.7 years (range, 0.1‐7.0 years), respectively. Previous OS differences in RTOG‐0129 persisted at 5 years. In RTOG‐0522, the 5‐year OS rates for the low‐risk, intermediate‐risk, and high‐risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5‐year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG‐0522 among a subgroup of patients considered to be at very good risk (p16‐positive disease, smoking history of ≤10 pack‐years, and classified with T1‐T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5‐year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group.
Conclusions
RTOG‐0129 risk groups persisted at 5 years and were reproducible in RTOG‐0522. However, there was variability in the estimates. These data underscore the importance of long‐term follow‐up and appropriate patient selection in therapeutic deintensification trials.
To the authors’ knowledge, the issue of whether Radiation Therapy Oncology Group (RTOG)‐0129 overall survival estimates for low‐risk, intermediate‐risk, and high‐risk groups are similar in other data sets or applicable to progression‐free survival is unknown. In the current study, RTOG‐0129 risk groups appear to persist at 5 years, are reproducible in RTOG‐0522, and can be applied to progression‐free survival. However, there is variability in the estimates, which underscores the importance of long‐term follow‐up in therapeutic deintensification.
Background
To test whether nomograms developed by NRG Oncology for oropharyngeal squamous cell carcinoma (OPSCC) patients could be validated in an independent population‐based sample.
Methods
The ...authors tested nomograms for estimating progression‐free survival (PFS) and overall survival (OS) in patients from the Veterans Health Administration with previously untreated locoregionally advanced OPSCC, diagnosed between 2008 and 2017, managed with definitive radiotherapy with or without adjuvant systemic therapy. Covariates were age, performance status, p16 status, T/N category, smoking history, education history, weight loss, marital status, and anemia. We used multiple imputation to handle missing data and performed sensitivity analyses on complete cases. Validation was assessed via Cox proportional hazards models, log‐rank tests, and c‐indexes.
Results
A total of 4007 patients met inclusion criteria (658 patients had complete data). Median follow‐up time was 3.20 years, with 967 progression events and 471 noncancer deaths. Each risk score was associated with poorer outcomes per unit increase (PFS score, hazard ratio HR, 1.42 1.37‐1.47; OS score, HR, 1.40 1.34‐1.45). By risk score quartile, 2‐year PFS estimates were 89.2%, 78.5%, 65.8%, and 48.3%; OS estimates were 92.6%, 83.6%, 73.9%, and 51.3%, respectively (P < .01 for all comparisons). C‐indices for models of PFS and OS were 0.65 and 0.67, for all patients, respectively (0.69 and 0.73 for complete cases). The nomograms slightly overestimated PFS and OS in the overall cohort but exhibited high agreement in complete cases.
Conclusions
NRG nomograms were effective for predicting PFS and OS for patients with OPSCC, supporting their broader applicability in the OPSCC population undergoing definitive radiotherapy.
Nomograms, including ones created by the Radiation Therapy Oncology Group (RTOG), can significantly refine prognostication, but previous attempts at external validation have been unsuccessful, possibly related to the handling of missing data. The RTOG nomograms generally performed well for prediction and risk‐stratification, especially in patients without missing data, but slightly overestimated progression‐free survival and overall survival in the overall population.
Objectives
Salivary gland adenoid cystic carcinoma (ACC) is rare, aggressive, and challenging to treat. Many ACCs have a t(6;9) chromosomal translocation resulting in a MYB‐NFIB fusion gene, but the ...clinical significance is unclear. The purposes of this study were to describe the clinicopathologic factors impacting survival and to determine the prevalence and clinical significance of MYB‐NFIB fusion.
Study Design
Case series.
Methods
Medical records of patients treated for ACC of the head and neck from 1974 to 2011 were reviewed and clinicopathologic data recorded. Fluorescence in situ hybridization (FISH) was used to detect MYB rearrangement in archival tumor tissue as a marker of MYB‐NFIB fusion.
Results
One hundred fifty‐eight patients were included, with median follow‐up 75.1 months. Median overall survival was 171.5 months (95% confidence interval CI = 131.9–191.6), and median disease‐free survival was 112.0 months (95% CI = 88.7–180.4). Advanced stage was associated with decreased overall survival (adjusted ptrend < 0.001), and positive margins were associated with decreased disease‐free survival (adjusted hazard ratio aHR = 8.80, 95% CI = 1.25–62.12, P = 0.029). Ninety‐one tumors were evaluable using FISH, and 59 (65%) had evidence of a MYB‐NFIB fusion. MYB‐NFIB positive tumors were more likely than MYB‐NFIB negative tumors to originate in minor salivary glands (adjusted prevalence ratios = 1.51, 95% CI = 1.07–2.12, P = 0.019). MYB‐NFIB tumor status was not significantly associated with disease‐free or overall survival (hazard ratio HR = 1.53, 95% CI = 0.77–3.02, P = 0.22 and HR = 0.91, 95% CI = 0.46–1.83, P = 0.80, respectively, for MYB‐NFIB positive compared with MYB‐NFIB negative tumors).
Conclusion
Stage and margin status were important prognostic factors for ACC. Tumors with evidence of MYB‐NFIB fusion were more likely to originate in minor salivary glands, but MYB‐NFIB tumor status was not significantly associated with prognosis.
Level of Evidence
4. Laryngoscope, 125:E292–E299, 2015
Most patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% ...of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, there are no molecular markers to identify patients with poor prognosis who would be harmed by de-escalation. Herein we report the clinical and genomic characteristics of persistent HPV-positive OPSCC after definitive platinum-based chemoradiation therapy.
Patients with HPV-positive OPSCC treated with curative intent platinum-based chemoradiation between 2007 and 2017 at two institutions and with a persistent locoregional disease were included. We evaluated clinical characteristics, including smoking status, age, stage, treatment, and overall survival. A subset of five patients had tissue available for targeted exome DNA sequencing and RNA sequencing. Genomic analysis was compared to a previously published cohort of 47 treatment-responsive HPV+ OPSCC tumors after batch correction. Mutational landscape, pathway activation, and OncoGPS tumor states were employed to characterize these tumors.
Ten patients met the inclusion criteria. The tumor and nodal stages ranged from T1 to T4 and N1 to N2 by AJCC 8th edition staging. All patients were p16-positive by immunohistochemistry, and eight with available
hybridization were confirmed to be HPV-positive. The 1-year overall survival from the time of diagnosis was 57%, and the 2-year overall survival was 17%.
mutations were present in three of five (60%) persistent tumors compared to 2% (one of 47) of treatment-responsive HPV-positive tumors (
= 0.008). Other genes with recurrent mutations in persistent HPV-positive OPSCC tumors were
,
,
, and
. Compared to treatment-responsive HPV-positive tumors, persistent tumors demonstrated activation of DNA Repair and p53, EMT, MYC, SRC, and TGF-beta signaling pathways, with post-treatment samples demonstrating significant activation of the PI3K-EMT-Stem pathways compared to pretreatment samples.
Chemoradiation-resistant HPV-positive OPSCC occurs infrequently but portends a poor prognosis. These tumors demonstrate higher rates of p53 mutation and activation of MYC, SRC, and TGF-beta pathways. A comparison of tumors before and after treatment demonstrates PI3K-EMT-Stem pathways post-treatment in HPV-positive tumors with persistent disease after platinum-based chemoradiation.
Objectives
Preoperative fine needle aspiration (FNA) of parotid lesions often is used in the initial evaluation of parotid masses, but its role in guiding surgical decision making remains unclear, in ...part due to varying diagnostic accuracy reported. We sought to evaluate the role of preoperative FNA in detection of malignancy and impact on surgical management.
Study Design
Retrospective study.
Methods
The medical records of patients who underwent parotidectomy at a single tertiary medical center were reviewed from 2000 to 2015. Patients who had a preoperative FNA comprised the study cohort.
Results
A total of 1,074 consecutive patients underwent parotidectomy during the study period; of those, 477 had a preoperative FNA. FNA was nondiagnostic in 26 cases. There were 29 false positives (6.4%), 26 false negatives (5.8%), 122 true positives (27.1%), and 274 true negatives (60.8%). The sensitivity and specificity of FNA were 82.4% and 90.4%, respectively, with a positive predictive value of 80.8% and a negative predictive value of 91.3%. The overall accuracy of preoperative FNA was 87.8%. The preoperative FNA resulted in a change in the surgical plan in 85 (18.9%) cases. In 66 of these cases (78%), surgery was extended to include neck dissection at time of resection. In 10 cases, FNA led to surgical management over surveillance. In 11 cases, FNA downgraded the extent of surgery planned to an excisional biopsy.
Conclusion
Preoperative FNA is a valuable adjunct in the surgical management of parotid lesions, with high specificity for the detection of malignant disease.
Level of Evidence
4. Laryngoscope, 128:398–402, 2018
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