FGFR Family Members Protein Expression as Prognostic Markers in Oral Cavity and Oropharyngeal Squamous Cell Carcinoma

Introduction Fibroblast growth factor receptor family member proteins (FGFR1-4) have been identified as promising novel therapeutic targets and prognostic markers in a wide spectrum of solid tumors. The present study investigates the expression and prognostic value of four FGFR family member proteins in a large multicenter oral cavity squamous cell carcinoma (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC) cohort. Methods Protein expression of FGFR1-4 was determined by immunohistochemistry on tissue microarrays containing 951 formalin-fixed paraffin embedded OCSCC and OPSCC tissues from the University Medical Center Utrecht and University Medical Center Groningen. Protein expression was correlated to overall survival using Cox regression models, and bootstrapping was performed as internal validation. Results FGFR proteins were highly expressed in 39-64 % of OCSCC and 63-79 % of OPSCC. Seventy-three percent (299/412) of OCSCC and 85 % (305/357) of OPSCC highly co-expressed two or more FGFR family member proteins. FGFR1 protein was more frequently highly expressed in human papillomavirus (HPV)-negative OPSCC than HPV-positive OPSCC (82 vs. 65 %; p = 0.008). Furthermore, protein expression of FGFR family members was not related to overall survival in OCSCC or OPSCC (p . 0.05). Conclusion FGFR family members are frequently highly expressed in OCSCC and OPSCC. These FGFR family member proteins are therefore potential targets for novel therapies that are urgently required to improve survival of OCSCC and OPSCC patients

Reproducibility and prognostic value of pattern of invasion scoring in low-stage oral squamous cell carcinoma

AimsTo evaluate and compare the prognostic value and reproducibility of different methods of pattern of invasion scoring in oral squamous cell carcinomas. The additional prognostic value to established histopathological prognostic factors was also analysed. Methods and resultsThe study group was confined to 211 previously untreated patients who underwent surgery for low-stage oral squamous cell carcinoma between 1997 and 2008. Median follow-up was 64months (range 0-193months). Pattern of invasion was scored using five previously described methods, at random and independently, by two observers. Pattern of invasion scoring showed moderate interobserver reproducibility (Cohen's =0.52-0.58). The predominant pattern of invasion and the summed predominant and worst pattern of invasion were independent prognosticators for locoregional recurrence-free survival (LRRFS) [hazard ratio (HR): 2.1, P=0.033 and HR 2.2, P=0.024, respectively] and disease-specific survival (DSS) (HR 2.3, P=0.032 and HR 2.1, P=0.044, respectively) in multivariate Cox regression analyses. The Harrell's C index for proven prognostic histopathological factors was 0.66 for LRRFS and 0.67 for DSS. This improved to 0.69 and 0.73 with the addition of pattern of invasion. ConclusionsPattern of invasion is an independent prognostic factor in low-stage oral squamous cell carcinoma. However, it has a moderate reproducibility, and the contributory value next to other prognostic histopathological factors is minimal

Addition of tumour infiltration depth and extranodal extension improves the prognostic value of the pathological TNM classification for early-stage oral squamous cell carcinoma

AIMS: In the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging Manual, tumor infiltration depth and extranodal extension are added to the pathological classification for oral squamous cell carcinoma. Currently available 8th TNM validation studies are lacking patients with conservative neck treatment, while changes in the classification especially affect patients with small tumors. This study's aim was to determine the potential impact of the changes within the 8th edition pTNM classification on the prognosis and treatment strategy of oral squamous cell carcinoma in a well-defined series of pT1-T2 patients with a long-term follow-up. METHODS AND RESULTS: 211 first primary pT1-T2 oral squamous cell carcinoma patients, with surgical resection as primary treatment were analyzed retrospectively. 173 patients received a neck dissection and 38 patients had a frequent clinical neck assessment. Long-term follow-up (median: 64 months) and reassessed tumor infiltration depth were available. Classification according to the 8th edition criteria resulted in 36% total upstaging with the T classification and 16% with N classification. T3 restaged patients (n=30, 14%) had lower 5-year disease specific survival rates compared to T2 staged patients (81% versus 67%, p = 0.042). Postoperative (chemo)radiotherapy could have been considered in another 7 (3%) patients based on the 8th edition criteria. CONCLUSIONS: Addition of tumor infiltration depth and extranodal extension within the 8th TNM classification leads to the identification of oral squamous cell carcinoma patients with a worse prognosis who might benefit from an improved postoperative treatment strategy. This article is protected by copyright. All rights reserved

Head and Neck Squamous Cell Carcinomas Do Not Express EGFRvIII

Purpose: To assess the prevalence of EGFRvIII, a specific variant of EGFR (epidermal growth factor receptor), in 3 well-defined cohorts of head and neck squamous cell carcinoma (HNSCC). Methods and Materials: Immunohistochemistry for the specific detection of EGFRvIII using the L8A4 antibody was optimized on formalin-fixed, paraffin-embedded tissue using glioblastoma tissue. It was compared with EGFR and EGFRvIII RNA expression using a specific reverse transcription-polymerase chain reaction also optimized for formalin-fixed, paraffin-embedded tissue. Tissue microarrays including 531 HNSCCs of various stages with complete clinicopathologic and follow-up data were tested for the presence of EGFRvIII. Results: None of the 531 cases showed EGFRvIII protein expression. Using an immunohistochemistry protocol reported by others revealed cytoplasmic staining in 8% of cases. Reverse transcription-polymerase chain reaction for the EGFRvIII transcript of the 28 highest cytoplasmic staining cases, as well as 69 negative cases, did not show expression in any of the tested cases, suggesting aspecific staining by a nonoptimal protocol. Conclusions: The EGFRvIII mutation is not present in HNSCC. Therefore, EGFRvIII does not influence treatment response in HNSCC and is not a usable clinical prognostic marker. (C) 2014 Elsevier Inc

Identification and validation of WISP1 as an epigenetic regulator of metastasis in oral squamous cell carcinoma

Lymph node (LN) metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC) patients. However, in approximately one third of OSCC patients nodal metastases remain undetected, and thus are not adequately treated. Therefore, clinical assessment of LN metastasis needs to be improved. The purpose of this study was to identify DNA methylation biomarkers to predict LN metastases in OSCC. Genome wide methylation assessment was performed on six OSCC with (N+) and six without LN metastases (N0). Differentially methylated sequences were selected based on the likelihood of differential methylation and validated using an independent OSCC cohort as well as OSCC from The Cancer Genome Atlas (TCGA). Expression of WISP1 using immunohistochemistry was analyzed on a large OSCC cohort (n = 5204). MethylCap-Seq analysis revealed 268 differentially methylated markers. WISP1 was the highest ranking annotated gene that showed hypomethylation in the N+ group. Bisulfite pyrosequencing confirmed significant hypomethylation within the WISP1 promoter region in N+ OSCC (P = 0.03) and showed an association between WISP1 hypomethylation and high WISP1 expression (P = 0.01). Both these results were confirmed using 148 OSCC retrieved from the TCGA database. In a large OSCC cohort, high WISP1 expression was associated with LN metastasis (P = 0.05), disease-specific survival (P = 0.022), and regional disease-free survival (P = 0.027). These data suggest that WISP1 expression is regulated by methylation and WISP1 hypomethylation contributes to LN metastasis in OSCC. WISP1 is a potential biomarker to predict the presence of LN metastases. (c) 2015 Wiley Periodicals, Inc

mTHPC-mediated Photodynamic Therapy of Early Stage Oral Squamous Cell Carcinoma:A Comparison to Surgical Treatment

<p>mTHPC-mediated photodynamic therapy (PDT) is used for treatment of early head and neck squamous cell carcinoma. This study is a retrospective comparison of PDT with transoral surgery in the treatment of early primary squamous cell carcinoma of the oral cavity/oropharynx.</p><p>PDT data were retrieved from four study databases; surgical results were retrieved from our institutional database. To select similar primary tumors, infiltration depth was restricted to 5 mm for the surgery group. A total of 126 T1 and 30 T2 tumors were included in the PDT group, and 58 T1 and 33 T2 tumors were included in the surgically treated group.</p><p>Complete response rates with PDT and surgery were 86 and 76 % for T1, respectively, and for T2 63 and 78 %. Lower local disease-free survival for PDT compared to surgery was found. However, when comparing the need for local retreatment, no significant difference for T1 tumors was found, while for T2 tumors surgery resulted in significantly less need for local retreatment. No significant differences in overall survival between surgery and PDT were observed.</p><p>PDT for T1 tumors results in a similar need for retreatment compared to surgery, while for T2 tumors PDT performs worse. Local disease-free survival for surgery is better than for PDT. This may be influenced by the benefit surgery has of having histology available. This allows an early decision on reintervention, while for PDT one has to follow a wait-and-see policy. Future prospective studies should compare efficacy as well as morbidity.</p>