Pretreatment pain predicts perineural invasion in patients with head and neck squamous cell carcinoma.

OBJECTIVES: Perineural invasion (PNI) in head and neck cancer (HNC) is a distinct pathological feature used to indicate aggressive tumor behavior and drive treatment strategies. Our study examined the prevalence and predictors of PNI in HNC patients stratified by tumor site. STUDY DESIGN AND METHODS: A retrospective analysis of head and neck squamous cell carcinoma (HNSCC) patients who underwent surgical resection at the University of Pittsburgh Medical Center between 2015 and 2018 was performed. Pretreatment pain was assessed at least 1 week before surgery using the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N). Demographics, clinical characteristics, and concomitant medications were obtained from medical records. Patients with cancers at the oropharynx and non-oropharynx (i.e., cancer at oral cavity, mandible, larynx) sites were separately analyzed. Tumor blocks were obtained from 10 patients for histological evaluation of intertumoral nerve presence. RESULTS: A total of 292 patients (202 males, median age = 60.94 ± 11.06) were assessed. Pain and PNI were significantly associated with higher T stage (p < 0.001) and tumor site (p < 0.001); patients with non-oropharynx tumors reported more pain and had a higher incidence of PNI compared to oropharynx tumors. However, multivariable analysis identified pain as a significant variable uniquely associated with PNI for both tumor sites. Evaluation of nerve presence in tumor tissue showed 5-fold higher nerve density in T2 oral cavity tumors compared to oropharyngeal tumors. CONCLUSIONS: Our study finds that PNI is associated with pretreatment pain and tumor stage. These data support the need for additional research into the impact of tumor location when investigating targeted therapies of tumor regression.

PIK3CA, HRAS and PTEN in human papillomavirus positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Recent genomic evidence suggests frequent phosphatidylinositide 3-kinase (PI3K) pathway activation in human papillomavirus (HPV) positive oropharyngeal squamous cell carcinoma. Mutations/amplification of the gene encoding p110α catalytic subunit of phosphoinositide 3-kinase (PIK3CA), loss of phosphatase and tensin homolog (PTEN) and HRAS mutations are known to activate PI3K pathway. METHODS AND RESULTS: PIK3CA mutations were identified by Sanger sequencing in 23 of 75 (31%) HPV-positive oropharyngeal carcinomas, including exon 9 (p.E545K [n = 10] and p.E542K [n = 5]) or exon 20 (p.H1047Y, n = 2) mutations. Five rare and one novel (p.R537Q) PIK3CA mutations were identified. HRAS mutation (p.Q61L) was detected in 1 of 62 tested cases. PIK3CA amplification by fluorescence in situ hybridization (FISH) was identified in 4 cases (4/21, 20%), while PTEN loss was seen in 7 (7/21, 33%) cases (chromosome 10 monosomy [n = 4], homozygous deletion [n = 3]). CONCLUSIONS: Overall, genetic alterations that likely lead to PI3K pathway activation were identified in 34 of 75 cases (45%) and did not correlate with disease specific survival. These findings offer a molecular rationale for therapeutic targeting of PI3K pathway in patients with HPV-positive oropharyngeal carcinoma.

Transoral Robotic Surgery and the Unknown Primary: A Cost-Effectiveness Analysis.

OBJECTIVE: To evaluate the cost-effectiveness of transoral robotic surgery (TORS) for the diagnosis and treatment of cervical unknown primary squamous cell carcinoma (CUP). STUDY DESIGN: Case series with chart review. SETTING: Tertiary academic hospital. SUBJECTS AND METHODS: A retrospective chart review was performed on patients with new occult primary squamous cell carcinoma of the head and neck with nondiagnostic imaging and/or endoscopy who were treated with TORS at a tertiary hospital between 2009 and 2012. Direct costs were obtained from the hospital's billing system, and national data were used for inpatient hospital costs and physician fees. The proportion of tumors found in 3 strategies was used as effectiveness to calculate the incremental cost-effectiveness ratio. RESULTS: In total, 206 head and neck robotic cases were performed at our institution between December 2009 and December 2012. Three surgeons performed TORS on 22 patients for occult primary squamous cell carcinoma. The primary tumor was located in 19 of 22 patients (86.4%). The incremental cost-effectiveness ratio for sequential and simultaneous examination under anesthesia with tonsillectomy (EUA) and TORS base of tongue resection was $8619 and $5774 per additional primary identified, respectively. CONCLUSION: Sequential EUA followed by TORS is associated with an incremental cost-effectiveness ratio of $8619 compared with traditional EUA alone. Bilateral base of tongue resection should be considered in the workup of these patients, particularly if the palatine tonsils have already been removed.

Early squamous cell carcinoma of the oral tongue: comparing margins obtained from the glossectomy specimen to margins from the tumor bed.

OBJECTIVES: To evaluate the impact of margin sampling on local recurrence in patients with pT1-2 pN0 conventional squamous cell carcinoma of the oral tongue. MATERIALS AND METHODS: Based on margin sampling, 126 cases were divided into group 1 (margins sampled from the glossectomy specimen only), group 2 (with revision of glossectomy margins), and group 3 (margins primarily sampled from the tumor bed). RESULTS: The probability of local progression-free survival at 3years was .90, .76 and .73 (p=.0389) in groups 1, 2, and 3, respectively. Groups differed by frequency of positive glossectomy specimen margins (p=<.0001) and by the average distance from carcinoma to the closest margin (4.5, 2.4, and 3.0mm for Groups 1, 2, and 3, respectively; p=.0009). Tumor bed margin status (positive vs. negative) and other parameters (e.g., pattern and depth of invasion) did not correlate with local recurrence. Status of the glossectomy specimen margins did correlate with outcome. A positive glossectomy margin conferred a relative risk of 2.5 (95% confidence interval, CI, 1 - 6.3) for local recurrence. A proportional hazards regression model for margin width found a hazard ratio of 0.67 (95% CI=.57-.98) comparable to a 33% decrease in risk of local recurrence for an increase of 1mm of margin width (p=.0271). CONCLUSIONS: Status of the glossectomy specimen margins rather than that of tumor bed margins was prognostically relevant. Reliance on tumor bed margins appears to be associated with worse local control, perhaps due to the narrower initial resection.

Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer.

PURPOSE: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. EXPERIMENTAL DESIGN: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m²) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1. RESULTS: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m², without dose-limiting toxicities; one patient treated at 1.3 mg/m² was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. CONCLUSIONS: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination.