Positive Oropharyngeal Squamous Cell Carcinoma Research Articles

Pathological Factors Predicting the Risk of Distant Failure for Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Pathological Factors Predicting the Risk of Distant Failure for Human Papillomavirus–Positive Oropharyngeal Squamous Cell Carcinoma (OPSCC)

Deregulation of SYCP2 predicts early stage human papillomavirus-positive oropharyngeal carcinoma: A prospective whole transcriptome analysis.

This study was designed to identify significant differences in gene expression profiles of human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OPSCC) and to better understand the functional and biological effects of HPV infection in the premalignant pathway. Twenty-four consecutive patients with locally advanced primary OPSCC were included in a prospective clinical trial. Fresh tissue samples (tumor vs. matched normal epithelium) were subjected to whole transcriptome analysis and the results validated on the same cohort with RT-quantitative real-time PCR. In a separate retrospective cohort of 27 OPSCC patients, laser capture microdissection of formalin-fixed, paraffin-embedded tissue allowed RNA extraction from adjacent regions of normal epithelium, carcinoma in situ (premalignant) and invasive SCC tissue. The majority of patients showed evidence of high-risk HPV16 positivity (80.4%). Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A/CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established (SFRP1, CRCT1, DLG2, SYCP2, and CRNN). Of these, SYCP2 showed the most consistent fold change from baseline in premalignant tissue; aberrant expression of this protein may contribute to genetic instability during HPV-associated cancer development. If further corroborated, this data may contribute to the development of a non-invasive screening tool. This study is registered with the UK Clinical Research Network (ref.: 11945).

Weekly cisplatin and radiotherapy for low risk, locoregionally advanced human papillomavirus-positive oropharyngeal squamous cell carcinoma.

There is interest in different treatment strategies, including deintensification in good prognosis human papillomavirus-positive (HPV(+)) oropharyngeal squamous cell carcinoma (SCC). We reviewed our experience with weekly cisplatin in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC since late 2009. Data from patients with low-risk HPV(+) oropharyngeal SCC treated with weekly cisplatin (40 mg/m(2) ) and 70 Gy radiotherapy were collected. Low risk was defined as stage III to IV oropharyngeal SCC excluding T1-2N1, T4 or N3 disease, or N2b to N2c disease in patients with >10 pack-year smoking history. Of 31 patients, the median age was 56 years (range, 41-69 years). All patients completed 70 Gy radiotherapy within 51 days and 84% completed at least 5 cycles of cisplatin. Grade 3 mucositis occurred in 22 patients (71%) and grade 3 febrile neutropenia in 6 patients (19%). No patients required enteral feeding at 12 months. The median follow-up was 30 months (range, 21-57 months) with no recurrences or deaths. Concurrent weekly cisplatin is relatively well-tolerated and associated with excellent disease control in low-risk, locoregionally advanced HPV(+) oropharyngeal SCC. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1117-E1121, 2016.

The value of follow-up FDG-PET/CT in the management and prognosis of patients with HPV-positive oropharyngeal squamous cell carcinoma.

To establish the accuracy of follow-up fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT and the impact of FDG PET/CT result on management decisions and patient outcome prediction (overall and progression free survival) in human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC). We included 96 HPV-positive oropharyngeal SCC (OPSCC) patients with 254 follow-up PET/CT scans in the study. The PET/CT result accuracy was established with histopathology or 6-month clinical follow-up as reference standard. The impact on change in management was established for each follow-up PET/CT scan. Overall survival was evaluated using Kaplan-Meier plots with a Log-rank test. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of the follow-up FDG-PET/CT were 97.0%, 92.5%, 67.0%, 99.5% and 93.1%, respectively. Follow-up PET/CT results were helpful in excluding tumour in 22% (9/41) of scans performed with prior clinical suspicion of disease and identified potential disease in 9.9% (21/213) scans performed without prior clinical suspicion. There was a change in management after 12.6% (32/254) scans. In 84.3% (214/254) scans, the patients were either observed or the same treatment was continued. The overall survival differed significantly between patients with a negative versus positive follow-up scan (log rank P < 0.001). The median progression free survival was 28 months, if the first follow-up scan performed within 6-12 months post-treatment completion was negative. Follow-up FDG PET/CT scans have an impact on the management plan and add value to clinical assessment in patients with HPV-positive OPSCC.

Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma.

Background:Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those with HPV-negative tumours. There is interest in de-escalating their treatment but strategies are needed for risk stratification to identify subsets with a poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) in relation to HPV tumour status and patient survival.Methods:Biopsies from 218 patients diagnosed with OPSCC between 2002 and 2011, who underwent chemo/radiotherapy were analysed for HPV by PCR, in-situ hybridisation and p16 immunohistochemistry (IHC). One hundred and thirty-nine samples with concordant HPV detection were analysed for CD3, CD4, CD8 and FoxP3 expression in tumour and stromal regions using multiplexIHC and multispectral image analysis. Labelling of smooth muscle actin (SMA) identified activated stroma.Results:Human papillomavirus-positive compared with HPV-negative OPSCC had higher infiltration in both tumour and stromal areas of CD4 and CD8 T cells but not FoxP3 T regulatory cells. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). There was significantly higher SMA expression in HPV-positive compared with -negative tumours, which did not correlate with survival.Conclusions:Studies of TILs for risk stratification in OPSCC should assess stromal infiltration.

Inter- and intra-observer variability in the classification of extracapsular extension in p16 positive oropharyngeal squamous cell carcinoma nodal metastases

Discern inter- and intra-observer variability in the classification of extracapsular extension (ECE) in p16+ oropharyngeal (OP) SCC comparing pathologists' own criteria versus those of a well-defined classification system. Five pathologists reviewed 50 digitally scanned nodal metastasis slides in three Rounds. Round One was by their own criteria as ECE present or absent, and Rounds Two and Three were with a defined ECE system: Grade 0 (no ECE), 0c (no ECE - thick capsule; no infiltration), 1 (ECE - cells beyond capsule), and 2 (soft tissue metastasis - cells in soft tissue without residual node). Round Three assessed intra-observer variability after an 8 month washout period. In Round One, all five agreed on only 48% of cases (n=24). Fleiss's Kappa value was 0.508 (95% CI: 0.357-0.644). For Rounds Two and Three, Grades 0 and 0c and Grades 1 and 2 were separately grouped as ECE absent or present. In Round Two, all five agreed on 68% of cases (n=34). Fleiss' Kappa was 0.635 (95% CI: 0.472-0.783), indicating statistically significantly better agreement. In Round Three, all five agreed on 64% of cases (n=32) giving a Fleiss's Kappa of 0.639. Pathologists agreed with their prior reads in approximately 90% of cases (average n=45.4, range n=42-49), an average intra-observer Cohen's Kappa of 0.8 (range: 0.68-0.95). Inter- and intra-observer variability rates for classification of soft tissue metastasis (ECE2) were substantially worse. There is substantial inter-, and modest intra-, observer variability among head and neck pathologists for ECE in p16+ OPSCC, which is modestly improved by a defined system.

Decision management in transoral robotic surgery: Indications, individual patient selection, and role in the multidisciplinary treatment for head and neck cancer from a European perspective.

Transoral robotic surgery (TORS) has become an accepted first-line treatment for T1 and T2 head and neck squamous cell carcinoma (HNSCC). The growing popularity of this procedure is the result of mounting skepticism as to the survival and quality of life (QOL) benefits of primary chemoradiation over definitive surgery, the rising incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) in progressively younger patients, and the advantages of TORS over transoral laser microsurgery (TOLM) and open surgery. The authors use their experience and data gained from the TORS-based management of >100 patients to establish a systematic approach to the use of TORS in HNSCC. This approach is constructed on a framework which goal is to select the primary treatment option that is most likely to reduce morbidity while preserving function and maintaining oncologic safety. A consensus regarding the indications of TORS and its role in the multidisciplinary management of HNSCC is to be established. © 2015 Wiley Periodicals, Inc. Head Neck 38: E2190-E2196, 2016.

In vitro 3-dimensional tumor model for radiosensitivity of HPV positive OSCC cell lines

The incidence of oropharyngeal squamous cell carcinoma (OSCC) is increasing due to the rising prevalence of human papillomavirus (HPV) positive OSCC. HPV positive OSCC is associated with better outcomes than HPV negative OSCC. Our aim was to explore the possibility that this favorable prognosis is due to the enhanced radiosensitivity of HPV positive OSCC. HPV positive OSCC cell lines were generated from the primary OSCCs of 2 patients, and corresponding HPV positive cell lines generated from nodal metastases following xenografting in nude mice. Monolayer and 3 dimensional (3D) culture techniques were used to compare the radiosensitivity of HPV positive lines with that of 2 HPV negative OSCC lines. Clonogenic and protein assays were used to measure survival post radiation. Radiation induced cell cycle changes were studied using flow cytometry. In both monolayer and 3D culture, HPV positive cells exhibited a heterogeneous appearance whereas HPV negative cells tended to be homogeneous. After irradiation, HPV positive cells had a lower survival in clonogenic assays and lower total protein levels in 3D cultures than HPV negative cells. Irradiated HPV positive cells showed a high proportion of cells in G1/S phase, increased apoptosis, an increased proliferation rate, and an inability to form 3D tumor clumps. In conclusion, HPV positive OSCC cells are more radiosensitive than HPV negative OSCC cells in vitro, supporting a more radiosensitive nature of HPV positive OSCC.

Interaction of quantitative (18)F-FDG-PET-CT imaging parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma.

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC) have a better survival than with HPV-negative oropharyngeal SCC. An (18) F-fluorodeoxyglucose positron emission tomography-CT ((18) F-FDG-PET-CT) may also provide prognostic information. We evaluated glycolytic characteristics in HPV-negative and HPV-positive oropharyngeal SCC. Forty-four patients underwent pretreatment (18) F-FDG-PET-CT. Standardized uptake values (SUVs) and metabolic active tumor volumes (MATVs) were determined for primary tumors. HPV status was determined with p16 immunostaining, followed by high-risk HPV DNA detection on the positive cases. Twenty-seven patients were HPV-positive (61.4%). Median MATV was 2.8 mL (range = 1.6-5.1 mL) for HPV-positive and 6.0 mL (range = 4.4-18.7 mL) for HPV-negative tumors (p < .001). SUV values are volume dependent (partial volume effect), therefore, MATV was included as covariate in multivariate analysis. In this multivariate analysis, the maximum SUV in HPV-positive tumors was 3.9 units lower than in HPV-negative tumors (p = .01). The (18) F-FDG-PET-CT parameters are lower in HPV-positive than in HPV-negative patients. Low pretreatment SUV values in HPV-positive oropharyngeal SCC may be at least partly explained by HPV-induced tumor changes.

Association of periodontitis and human papillomavirus in oral rinse specimens: Results from the National Health and Nutrition Survey 2009-2012

BackgroundHuman papillomavirus (HPV)–positive oropharyngeal squamous cell carcinomas are increasing in incidence and are becoming significant public health concerns. Periodontitis is a chronic condition in which the affected tissue may facilitate oral HPV infection and persistence. The purpose of this study was to determine if an association of the presence of HPV in oral rinse specimens and periodontal disease exists. MethodsThe authors combined the National Health and Nutrition Examination Survey (NHANES) data for years 2009-2010 and 2011-2012. The authors included participants aged 30-69 years who had clinically assessed periodontal and HPV data (n = 6,004). The authors analyzed the data using the Rao-Scott χ2 test and logistic regression. ResultsThere were 498 participants who had the presence of HPV in oral rinse specimens. The adjusted odds ratio for the presence of HPV in oral rinse specimens with relation to periodontal disease was 1.04 (95% confidence interval, 0.63-1.73), adjusting for sex, race and ethnicity, education, age, income-to-poverty ratio, smoking, alcohol use, and number of sex partners during their lifetime. ConclusionsThe authors failed to reject the hypothesis of no association of the presence of HPV in oral rinse specimens and periodontitis. Practical ImplicationsAlthough oral HPV infection is a serious concern, the authors found that periodontitis was not shown to be related to the presence of HPV in oral rinse specimens in adjusted analyses in this study.

Epigenetic Mechanisms of Human Papillomavirus-Associated Head and Neck Cancer.

Growing evidence suggests that as many as half of all oropharyngeal squamous cell carcinomas (OPSCCs) harbor human papillomavirus (HPV) infections. Despite being more advanced at diagnosis, HPV-positive OPSCCs are associated with a better response to therapy and longer patient survival than HPV-negative OPSCCs. Human papillomavirus-positive OPSCC has also been shown to have distinct host gene expression profiles compared with HPV-negative OPSCC. Recently, this distinction has been shown to include the epigenome. It is well supported that cancers are epigenetically deregulated. This review highlights epigenetic differences between HPV-positive and HPV-negative OPSCCs. The epigenetic mechanisms highlighted include methylation changes to host and viral DNA, and host chromatin modification. We also review the current evidence regarding host DNA methylation changes associated with smoking, and deregulation of microRNA expression in HPV-positive OPSCC. To provide an overview of epigenetic mechanisms reported in HPV-positive OPSCC, with analogies to cervical cancer, and discussion of the challenges involved in studying epigenetic changes in HPV-associated OPSCC in combination with changes associated with smoking. Sources were a literature review of peer-reviewed articles in PubMed on HPV and either OPSCC or head and neck squamous cell carcinoma, and related epigenetic mechanisms. Epigenetic changes are reported to be a contributing factor to maintaining a malignant phenotype in HPV-positive OPSCC. The epigenetic mechanisms highlighted in this review can be studied for potential as biomarkers or as drug targets. Furthermore, continued research on the deregulation of epigenetic mechanisms in HPV-positive OPSCC (compared with HPV-negative OPSCC) may contribute to our understanding of the clinical and biologic differences between HPV-positive and HPV-negative OPSCC.

Using Texture Analysis to Determine Human Papillomavirus Status of Oropharyngeal Squamous Cell Carcinomas on CT.

Human papillomavirus-associated oropharyngeal squamous cell carcinoma is increasing in prevalence and typically occurs in younger patients than human papillomavirus-negative squamous cell carcinoma. While imaging features of human papillomavirus-positive versus human papillomavirus-negative squamous cell carcinoma nodal metastases have been described, characteristics distinguishing human papillomavirus-positive from human papillomavirus-negative primary squamous cell carcinomas have not been well established. The purpose of this project was to evaluate the use of texture features to distinguish human papillomavirus-positive and human papillomavirus-negative primary oropharyngeal squamous cell carcinoma. Following institutional review board approval, 40 patients with primary oropharyngeal squamous cell carcinoma and known human papillomavirus status who underwent contrast-enhanced CT between December 2009 and October 2013 were included in this study. Segmentation of the primary lesion was manually performed with a semiautomated graphical-user interface. Following segmentation, an in-house-developed texture analysis program extracted 42 texture features from each segmented volume. A t test was used to evaluate differences in texture parameters between human papillomavirus-positive and human papillomavirus-negative squamous cell carcinomas. Of the 40 included patients, 29 had human papillomavirus-positive oropharyngeal squamous cell carcinoma and 11 had human papillomavirus-negative oropharyngeal squamous cell carcinoma. Significant differences were seen in the histogram parameters median (P = .006) and entropy (P = .016) and squamous cell carcinoma entropy (P = .043). There are statistically significant differences in some texture features between human papillomavirus-positive and human papillomavirus-negative oropharyngeal tumors. Texture analysis may be considered an adjunct to the evaluation of human papillomavirus status and characterization of squamous cell carcinoma.

IGSF4 methylation as an independent marker of human papillomavirus-positive oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV) is a known causative agent for oropharyngeal squamous cell carcinoma (OPSCC). Whereas it is becoming more firmly established that HPV-positive head and neck squamous cell carcinoma is associated with better survival outcomes, believed to be because of better response to chemoradiation therapy, the specific mechanisms for these improved survival outcomes remain underexplored. To examine the relationship between HPV status and promoter methylation in an OPSCC cohort. Real-time quantitative polymerase chain reaction was used to examine oncogenic HPV type 16 in a retrospective cohort of 121 patients with primary OPSCC. Aberrant promoter methylation of IGSF4, DAPK1, and ESR1 genes, known to be methylated in head and neck squamous cell carcinoma, including OPSCC, was examined by means of quantitative methylation-specific polymerase chain reaction. Patients received standard therapy. Univariate associations between HPV and methylation were analyzed using Fisher exact tests followed by multivariable logistic regression. Cox proportional-hazards regression was used to model the risk of death given age, race, sex, HPV status, methylation, stage, smoking, and treatment. In univariate logistic regression analyses, HPV-positive status was significantly associated with Caucasian race (P = .02), treatment (radiotherapy only, P = .01; chemoradiotherapy, P = .007), and IGSF4 methylation (P = .005). The final multivariate logistic model, after controlling for patient characteristics (sex, age, smoking, race, and treatment) with backward variable selection among genes, retained IGSF4 methylation (OR, 4.5 [95% CI, 1.6-12.8]; P = .005), Caucasian race (OR, 2.9 [95% CI, 1.0-8.3]; P = .053), treatment (radiotherapy only vs neither: OR, 11.62 [95% CI, 2.02-66.82]; P = .02; chemoradiotherapy vs neither: OR, 11.15 [95% CI, 1.92-64.65]; P = .01), male sex (OR, 4.7 [95% CI, 1.3-17.0]; P = .02), and younger age (OR, 0.9 [95% CI, 0.90-1.0]; P = .008) as independent predictors of HPV-positive status. Cox regression modeling indicated HPV-negative status, age, male sex, smoking, and radiation treatment as independent predictors of mortality. Methylation of IGSF4 is an independent predictor of HPV-positive status. DNA methylation in conjunction with HPV infection appears to play a role in OPSCC.

Quantitative diffusion-weighted MRI parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma.

Patients with human papillomavirus-positive oropharyngeal squamous cell carcinomas have a better survival rate than those with human papillomavirus-negative oropharyngeal squamous cell carcinomas. DWI characterizes biologically relevant tumor features, and the generated ADC may also provide prognostic information. We explored whether human papillomavirus status and ADC values are independent tumor characteristics. Forty-four patients with oropharyngeal squamous cell carcinomas underwent pretreatment DWI. ADC values for the primary tumors were determined by using 3 b-values in an ROI containing the largest area of solid tumor on a single section of an axial DWI image. Human papillomavirus status was determined with p16 immunostaining, followed by high-risk human papillomavirus DNA detection on the p16-positive cases. Twenty-two patients were human papillomavirus-positive (50.0%). ADC values were not significantly different between human papillomavirus-negative (ADC(mean) = 1.56 [1.18-2.18] × 10(3) mm(2)/s) and human papillomavirus-positive tumors (ADC(mean) = 1.46 [1.07-2.16] × 10(3) mm(2)/s). No significant association between ADC and human papillomavirus status was found in oropharyngeal squamous cell carcinomas. In our study population, differences in genetic and histologic features between human papillomavirus-positive and human papillomavirus-negative oropharyngeal squamous cell carcinomas did not translate into different ADC values. Long-term follow-up studies are needed to establish whether ADC has prognostic value and whether this is independent of the human papillomavirus status.

Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is recognized as a distinct disease entity associated with improved survival. DNA hypermethylation profiles differ significantly by HPV status suggesting that a specific subset of methylated CpG loci could give mechanistic insight into HPV-driven OPSCC. We analyzed genome-wide DNA methylation of primary tumor samples and adjacent normal mucosa from 46 OPSCC patients undergoing treatment at Montefiore Medical Center, Bronx, NY using the Illumina HumanMethylation27 beadchip. For each matched tissue set, we measured differentially methylated CpG loci using a change in methylation level (M value). From these analyses, we identified a 22 CpG loci panel for HPV+ OPSCC that included four CDKN2A loci downstream of the p16(INK4A) and p14(ARF) transcription start sites. This panel was significantly associated with overall HPV detection (P < 0.05; ROC area under the curve = 0.96, 95% CI: 0.91–1.0) similar to the subset of four CDKN2A-specific CpG loci (0.90, 95% CI: 0.82–0.99) with equivalence to the full 22 CpG panel. DNA hypermethylation correlated with a significant increase in alternative open reading frame (ARF) expression in HPV+ OPSCC primary tumors, but not to the other transcript variant encoded by the CDKN2A locus. Overall, this study provides evidence of epigenetic changes to the downstream region of the CDKN2A locus in HPV+ oropharyngeal cancer that are associated with changes in expression of the coded protein products.

Pre-radiotherapy feeding tube identifies a poor prognostic subset of postoperative p16 positive oropharyngeal carcinoma patients.

BackgroundThis study explores variables associated with poor prognosis in postoperative p16 positive oropharyngeal squamous cell carcinoma (OPSCC) patients undergoing adjuvant radiotherapy or chemoradiotherapy. Specifically, analysis was done related to timing of feeding tube insertion relative to radiotherapy.MethodsFrom 1997–2009, of 376 consecutive patients with OPSCC, 220 received adjuvant IMRT, and 97 were p16 positive and eligible. Of these, 23 had feeding tube placement before IMRT (B-FT), 32 during/after IMRT (DA-FT), and 42 had no feeding tube (NO-FT). Feeding tubes were not placed prophylactically. These three groups were analyzed for differential tumor, patient, treatment, and feeding tube characteristics, as well as differences in overall survival (OS), disease free survival (DFS), and distant metastasis free survival (DMFS).ResultsPre-RT FT insertion was associated with higher tumor size and depth, T (but not N) and overall stage, comorbidities, presence of chemotherapy, and less use of transoral laser microsurgery/transoral bovie. Additionally, time from surgery to IMRT completion was also statistically longer in the B-FT group. The feeding tube was permanent in 52% of patients in the B-FT group versus 16% in the DA-FT group (p = 0.0075). The 5-year OS for the NO-FT, DA-FT, and B-FT groups was 90%, 86%, and 50%, respectively. The 5-year DFS for the NO-FT, DA-FT, and B-FT groups was 87.6%, 83.6%, and 42.7%, respectively. Multivariate analysis showed that for OS and DFS, feeding tube placement timing and smoking history were statistically significant.ConclusionDue to the poor prognosis of early FT insertion, the presence of FTs at time of radiotherapy consultation can be used as an alternate marker to identify a subset of p16 positive OPSCC patients that have a poor prognosis.

Oropharyngeal squamous cell carcinoma (OPSCC), a practical prognostic immunophenotypic panel

Aims Human papillomavirus (HPV)-positive OPSCC accounts for 25% of OPSCC. HPV E6 and E7 proteins inactivate the retinoblastoma gene causing overexpression of the p16 protein, which is regarded as HPV surrogate. There is evidence that p16 expression is an independent prognostic factor and cyclin D1 overexpression associated with poor prognosis in OPSCC. HPV+ OPSCC carries better prognosis than HPV–OPSCC, and is characterised by histological poor squamous differentiation (PD) and advanced regional nodal metastasis. This study aimed to study correlation among the morphology, immunophenotype and HPV DNA in OPSCC. Methods The morphology, immunophenotype and HPV DNA in OPSCC of 147 patients in Hong Kong were studied, using an immunoautostainer (p16 and cyclin D1), polymerase chain reaction and typing by sequencing for HPV DNA detection. Results Twenty-seven (18%) tumours carried HPV16 DNA, 56 (38%) were p16+ and 105 (72%) cyclin D1+. Fifty-two (35%) were PD tumours. Strong statistical correlation (p Discussion This study showed that p16 is strongly correlated with the good prognostic feature PD, while cyclin D1 is correlated with the poor prognostic features p16– and HPV DNA–. We conclude a simple immunophenotypic panel of p16 and cyclin D1 is a practical approach for prognostication of HPV+ OPSCC.

Receptor tyrosine kinase profiles and human papillomavirus status in oropharyngeal squamous cell carcinoma.

Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OSCCs) are two distinct entities. We defined the molecular profiles of druggable receptor tyrosine kinases (RTKs) in both groups. E5 expression and RTK alterations were studied in 17 HPV-positive and 59 HPV-negative formalin-fixed OSCCs. RTK activation was explored in further 12 frozen OSCCs. The HPV-positive OSCCs showed E5 expression and 33.3% expressed low level of HER2. The HPV-negative OSCCs showed HER2 expression (31.2%), increased HER2 gene copy number (46.51%, P=0.045) and HER2 activation through HER2/EGFR heterodimerisation; HER3 (51.06%, P=0.008) and neuregulin (65.63%; P=0.03) expression, HER3 activation and HER3/EGFR heterodimerisation; and increased IGF-1R copy number (40.50%, P=0.021), high IGF-1R cDNA values (P= 0.002), IGF-1R activation and expression of IGF1/2 and amphiregulin. PI3KCA mutations/expression/increased gene copy number and PTEN mutations were found in both groups, whereas PTEN gene loss was only observed in the HPV-positive cases. Human papillomavirus-positive and HPV-negative OSCC showed different RTK profiles. In HPV-positive cases, it would be interesting to study the expression of E5, which may modulate EGFR turnover and activate VEGF and PDGFRβ. In HPV-negative cases, HER3 may be a promising druggable biomarker that deserves further investigation. PI3KCA and PTEN alterations encourage the promising clinical evaluation of PI3K/mTOR inhibitor activity in OSCC, particularly in HPV-positive/PI3KCA-mutated OSCCs because they may be driven by PI3KCA mutation alone.

Outcomes of P16 positive oropharyngeal squamous cell carcinoma treated with surgery and adjuvant IMRT

Objectives This study compares the outcomes of patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with surgery followed by adjuvant radiotherapy (aRT) or chemoradiotherapy (aCRT).

Abstract A89: Racial disparity in p16 positive oropharyngeal squamous cell carcinoma

Abstract Oropharyngeal squamous cell carcinoma (OPSCC) has become increasingly prominent. Studies have definitively established a causal relationship between HPV and squamous cell carcinoma of the oropharynx. Up to 95% of HPV positive OPSCC patients are also positive for p16 as determined by immunohistochemical (IHC) methods. Previous research has indicated that HPV positive OPSCC patients have a more favorable prognosis. For this reason, p16 status is emerging as an important consideration during risk stratification when predicting OPSCC patient survival. The majority of studies indicating that p16+ OPSCC patient prognosis is improved are based on research designed to represent a general population. This project examines the influence of p16 positivity on patient prognosis in a retrospective cohort population of 120 patients with OPSCC. Furthermore, this project examines whether these findings are present in different racial/ethnic groups, when other variables, such as disease stage, age, gender and smoking history are similar. These results may lead to better disease management and tailoring treatment taking into consideration the HPV status in OPSCC. Methods: A retrospective cohort of patients from our hospitals with OPSCC was studied. A database was formed to organize history and outcomes for each of the patients. Overall survival (OS) was measured based on months of survival from time of diagnosis to death. Censored data was used to consider patients followed for different lengths of time or lost to follow up. 120 patients, on whom p16 data was available were grouped in 60 African-American (AA) and 60 Caucasian (CA). The 2 groups were matched for stage of disease. Kaplan Meier survival curves were produced to compare OS between 60 AA (31 p16+, 29 p16 -) and 60 CA (35 p16+, 25p16-). The Cox Proportional Model was used in a multivariate analysis in comparing these 2 groups to control for gender, age, tobacco use history, stage of disease at diagnosis and the type of treatment received: radiation and chemotherapy. SPSS version 21 was used for final statistical analysis. Results: CA patients, on univariate analysis showed improved overall survival in p16+ individuals (figure A1. p &amp;lt;.0001). A multivariate analysis also indicated statistically significant differences between p16+ and p16- CA and showed improved survival for those that were p16 + (figure B1. p=.004). AA patients did not show improved survival when p16 positive, by univariate analysis (figure C1. p=.612). A multivariate analysis supported these results by demonstrating that there were no significant overall survival differences between p16+ and p16- AA patients (figure D1. p = .645). Conclusions: 1. This study is in concordance with existing data in the literature, showing improved survival for p16 positive patients only in this studied CA group. 2. However, the benefit of improved survival for p16+ OPSCC was unexpectedly lost in AA patients in this studied group and further studies need to be undertaken to better understand the apparently different disease development. 3. When treating patients with OPSCC racial/ethnic factors should be considered, in addition to p16 status. Citation Format: Gabriela M. Oprea-Ilies, Charles Moore, Mylar Joseph Giri, Andrew J. Page, Shruti K. Rereddy, Bhagirath Majmudar, Susan Muller. Racial disparity in p16 positive oropharyngeal squamous cell carcinoma. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr A89. doi:10.1158/1538-7755.DISP13-A89