Tumor cells were first shown to exhibit a distinct metabolic phenotype over 80 years ago. Since then, it has become clear that multiple oncogenic events contribute to the development of a metabolic phenotype which supports rapid proliferation. Because this phenotype represents an essential component of tumorigenesis and disease progression it also represents a potential source of biomarkers associated with aggressive disease. In addition, the addiction of tumor cells to specific nutrients, and the up-regulation of key metabolic enzymes provide unique opportunities for pharmacologic manipulation. Despite the use of multimodality treatment, survival rates for patients with advanced HNSCC remain low, partially due to the development of drug resistance. In this review, we evaluate the role of altered HNSCC metabolism as both a source of novel biomarkers and a means to bypass resistance mechanisms to conventional forms of therapy.
Adenoid cystic carcinoma (ACC) is an unusual salivary gland malignancy that remains poorly understood. Standard treatment, including surgery with postoperative radiation therapy have attained reasonable local control rates, but the propensity for distant metastases has limited any improvement in survival over time. Our understanding of the molecular mechanisms driving adenoid cystic carcinoma is quite rudimentary, due to the infrequent nature of its occurrence.
An extensive literature review was performed on salivary gland adenoid cystic carcinoma and basic science research findings.
This review highlights many findings that are emerging about the carcinogenesis of ACC including cytogenetics, tumor suppressor genes, oncogenes, epigenetic alterations, mitochondrial alterations, and biomarker studies.
While there have been many discoveries, much still remains unknown about this rare malignancy.
molecular; genetics; DNA; adenoid cystic carcinoma
Tissue imprinting can generate molecular marker maps of tumor cells at deep surgical margins. This study evaluates the feasibility of this method for detection of residual head and neck squamous cell carcinoma (HNSCC).
Paired fresh tissue and nitrocellulose membrane imprints of tumor and deep margins were collected from 17 HNSCC resections. DNA was amplified using quantitative methylation-specific PCR (qMSP) for p16, DCC, KIF1A, and EDNRB. Levels of methylation in tumors and deep margins were compared.
DNA from imprints was adequate for qMSP. Hypermethylation of target genes was present in 12/17 tumors and in 8 deep margins. Methylation level was better from margin imprints than tissue. During follow-up (median 13 months), local or regional recurrences occurred in six cases of which five had molecularly positive margins.
Tissue imprinting is feasible for molecular detection of residual tumor at deep surgical margins and may correlate with locoregional recurrence.
Tissue imprint; head and neck squamous cell carcinoma; deep surgical margin; molecular diagnosis; quantitative methylation-specific PCR; Imprint; Deep margin; Surgery; Recurrence
Oropharyngeal cancers are increasingly associated with human papillomavirus (HPV). Little is known about the experience of patients receiving this diagnosis.
Semi-structured interviews were conducted with 10 survivors of HPV-related oropharynx cancer. The interviews were transcribed and recurring themes were identified.
Physicians were a trusted source of information regarding HPV. Framing the diagnosis in terms of prognosis resonated with patients. The uncertainty about transmission, latency, and communicability colored the dialogue about HPV. Despite some understanding of prevalence and transmission, patients worried about their partner’s risk. Patients sought information about HPV on the internet, but it was not easily navigable. Emotional reactions to the diagnosis remained mostly cancer-centric rather than HPV-centric. A patient education handout was developed in response to patient questions.
Additional educational resources explaining the facts about HPV in HNSCC in a consistent way including content of highest priority to patients may improve understanding of HPV.
Human papillomavirus (HPV); oropharynx; patient education; quality of life; patient communication
Few human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) cell lines exist. We established UM-SCC-104, a new HPV(+) HNSCC cell linefrom a recurrent oral cavity tumor, and characterized it for the presence of cancer stem cells (CSC).
Tumor cells were tested for biomarker expression by immunohistology and the presence of HPV was assessed by several methods.
UM-SCC-104 has a unique genotype, contains HPV-16 and expresses E6/E7. Inoculation of (Aldehyde Dehydrogenase) ALDH(+) and ALDH(−) cells in an immunocompromised mouse resulted in tumor growth from the ALDH(+) cells after 6 weeks that recapitulated the histology of the primary, while ALDH(−) cells did not produce tumors.
UM-SCC-104, a new HPV-16, CSC-containing HNSCC cell line will aid in studying recurrent HPV(+) tumors. The aggressive nature of this tumor is consistent with high uniform expression of EGFR and a functionally significant proportion of ALDH(+) CSC.
HNSCC; HPV; cancer stem cells; head and neck cell lines; ALDH
Dysphagia is a potential consequence of treatment for head and neck cancer. Neuromuscular electrical stimulation (NMES) has evolved as a treatment option, with the goal of improved swallow function in patients with chronic dysphagia. However, the effects of NMES on tumorigenicity are unknown and often confound the initiation of this therapy, potentially limiting its efficacy in treating patients with head and neck cancer.
Squamous cell carcinoma was grown in the flank of athymic, nude mice. Mice were randomized into treatment and control groups; the experimental group received daily NMES directly to the flank for 8 days.
Tumor volumes, recorded on days 0, 3, 7, and 10, demonstrated no significant differences between groups on each day of measurement. Immunohistochemical analysis of apoptosis, proliferation, and vascularization also failed to demonstrate statistically significant differences between treated and untreated groups.
NMES does not promote the growth of underlying tumor in our model. These data may provide preliminary evidence that applying electrical stimulation over the muscles of the anterior neck does not increase the risk of tumorigenicity. Early initiation of NMES in this challenging population may be feasible from an oncologic standpoint.
NMES; electrical stimulation; VitalStim; squamous cell carcinoma; dysphagia
The objective of this study was to determine the prognostic significance of viable tumor in post-chemoradiation neck dissection specimens in patients with squamous cell carcinoma of the laryngopharynx.
Retrospective analysis identified 181 patients treated with primary concurrent chemoradiation for carcinoma of the laryngopharynx at Memorial Sloan-Kettering Cancer Center between the years 1995 and 2005. Of these, 56 patients had a comprehensive neck dissection either as a planned or salvage procedure. Neck dissection specimens were analyzed by a single pathologist for the presence of viable tumor. The presence of viable tumor was correlated to the timing of neck dissection after chemoradiation and to tumor response. Overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were determined by the Kaplan–Meier method, and correlation to tumor viability was determined with the log-rank test.
Nineteen (33%) patients had viable tumor in their neck dissection specimens. Viable tumor was higher in patients who had a less-than-complete response to chemoradiation compared with those who had a complete response (42% vs 25%, p = .1). There was no correlation to timing of neck dissection. The 5-year OS, DSS, and RFS were significantly lower in patients who had viable tumor in their neck dissection specimens (OS 49% vs 93%, p = .0005; DSS 56% versus 93%, p = .003; RFS 40% vs 75%, p = .004).
Patients with viable tumor in postchemoradiation neck dissection specimens had a poorer outcome compared with patients with no viable tumor.
viable tumor; chemoradiation; neck dissection; prognosis
Minimally invasive video-assisted thyroidectomy (MIVAT) advantages include a smaller incision, less extensive surgical dissection, improved visualization secondary to rigid fiberoptics, and decreased postoperative pain. The aims of our study were to report our experience using expanded indications of MIVAT.
A retrospective chart review of a single surgeon's initial experience was carried out at a tertiary academic cancer center.
In all, 53 patients were identified, of whom 40 underwent total thyroidectomy and 13 underwent hemithyroidectomy. Thyroid volume, nodule size, incision length, and surgical time were all examined. Most common pathology was well-differentiated papillary thyroid cancer (69.8%): 42% of patients had evidence of thyroiditis found on pathology; 17% of patients had temporary vocal cord paralysis, with only 1 case of vocal cord paralysis persisting >6 months (1.9%). Six patients (11%) experienced temporary hypocalcemia, requiring postoperative calcium supplementation; no patients experienced permanent hypocalcemia.
The use of MIVAT with expanded indications shows complication rates comparable to those of traditional open thyroidectomy.
thyroid; minimally invasive; thyroidectomy; thyroid neoplasm; video-assisted surgery
Cancers of the head and neck are associated with detriments in health-related quality of life (HRQOL), however little is known about different experiences between African Americans and non-Hispanic whites.
HRQOL was measured by the Functional Assessment of Cancer Therapy – Head and Neck approximately five months post diagnosis among 222 cancer patients from North Carolina. Higher scores represent better HRQOL. Regression models included sociodemographic characteristics and clinical factors.
African Americans reported higher Physical Well-Being than Caucasians (adjusted means 23.1 vs 20.9). African Americans with incomes <$20,000 reported higher Emotional Well-Being (21.4) and fewer head and neck symptoms (22.0). Non-Hispanic whites making <$20,000 reported the poorest Emotional Well-Being (17.3) while African Americans making >$20,000 reported the most head and neck symptoms (18.7).
Further investigation is needed to explore variation in HRQOL experiences among different race and socio-economic groups that may inform resource allocation to improve cancer care.
health-related quality of life; head and neck cancer; African Americans
fMRI; swallowing; neuroimaging; neuroplasticity; dysphagia
The transformation of the upper aerodigestive tract – oral cavity, pharynx and larynx – serves the functions of eating, speaking and breathing during sleeping and waking hours. These life-sustaining functions may be produced by a central neural sensorimotor system that shares certain neuroanatomic networks while maintaining separate neural functional systems and network structures. Current understanding of development, maturation, underlying neural correlates and integrative factors are discussed in light of currently available imaging modalities and recently emerging interventions. Exercise and an array of additional treatments together appear to provide promising translational pathways for evidence-based innovation, novel habilitation and rehabilitation strategies and delay, or even prevent neuromuscular decline cross-cutting functions and supporting quality of life throughout increasingly enduring lifespans.
dysphagia; dysarthria; obstructive sleep apnea; sarcopenia; exercise; neural maturation; neuromuscular plasticity
We performed a pilot study using Trojan vaccines in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). These vaccines are composed of HLA-I and HLA-II restricted melanoma antigen E (MAGE)-A3 or human papillomavirus (HPV)-16 derived peptides, joined by furin-cleavable linkers, and linked to a “penetrin” peptide sequence derived from HIV-TAT. Thirty-one patients with SCCHN were screened for the trial and 5 were enrolled.
Enrolled patients were treated with 300 lg of Trojan peptide supplemented with Montanide and granulocyte-macrophage colony-stimulating factor (GM-CSF) at 4-week intervals for up to 4 injections.
Following vaccination, peripheral blood mononuclear cells (PBMCs) from 4 of 5 patients recognized both the full Trojan constructs and constituent HLA-II peptides, whereas responses to HLA-I restricted peptides were less pronounced.
This treatment regimen seems to have acceptable toxicity and elicits measurable systemic immune responses against HLA-II restricted epitopes in a subset of patients with advanced SCCHN.
SCCHN; vaccine; HLA-I; HLA-II; immune response
In cancer, tumor escape from the host immune system includes apoptosis of circulating CD3+CD8+ effector T lymphocytes. Here, we compare sensitivity to apoptosis of virus- with tumor-specific circulating CD8+ T cells in patients with head and neck cancer.
Wild-type p53 peptide-specific (p53264-272 and p53149-157) and viral peptide-specific (EBV BMLF259-267 and CMVpp65495-503) tetramers were used to measure the frequency of reactive T cells by flow cytometry. Annexin V (ANX) binding to circulating 7-amino-actinomycin D-negative but tetramer+CD8+ T cells in PBMC obtained from 21 patients with head and neck cancer and 11 normal controls (NC) was evaluated.
In patients with head and neck cancer, a higher percentage of tetramer+CD8+ than tetramer−CD8+ T cells bound ANX (p < .023–.005). Although most tumor-epitope+CD8+ T cells bound ANX, lower percentages of virus-specific CD8+ T cells were ANX+ in the same patients.
Preferential demise of circulating tumor-specific CD8+ T cells and their paucity in head and neck cancer contribute to tumor escape.
apoptosis; tetramers; effector T lymphocytes; tumor antigen-specific T cells
Nasopharyngeal carcinoma with leptomeningeal involvement is rare and typically has poor prognosis.
Methods and Results
We present a case report of a patient with nasopharyngeal carcinoma who was treated with high-dose intravenous methotrexate and remains asymptomatic and without clinical evidence of disease 6 years later.
Systemic high-dose methotrexate should be evaluated in the treatment of advanced nasopharyngeal carcinoma with central nervous involvement.
methotrexate; nasopharyngeal carcinoma; leptomeningeal disease; CNS involvement; high-dose methotrexate
Scientific innovation has enabled whole exome capture and massively parallel sequencing of cancer genomes. In head and neck cancer, next-generation sequencing has granted us further understanding of the mutational spectrum of squamous cell carcinoma. As a result of these new technologies, frequently occurring mutations were identified in NOTCH1, a gene that had not previously been implicated in head and neck cancer. The current review describes the most common mutations in head and neck cancer: TP53, NOTCH1, HRAS, PIK3CA, and CDKN2A. Emphasis is placed on the involved cellular pathways, clinical correlations, and potential therapeutic interventions. Additionally, the implications of human papillomavirus on mutation patterns are discussed.
next generation sequencing; mutations; oncogene; tumor suppressor gene; head and neck squamous cell carcinoma
To assess volumetric changes of human papillomavirus (HPV)-related lymph nodes (LN) before, during, and after a course of intensity-modulated radiation therapy (IMRT) ± chemotherapy.
Each “pathologic” LN (≥1 cm) was contoured on the available diagnostic/planning CTs before, during each week, and after treatment.
Seventy-nine LNs in 50 patients were identified. Beyond the first week of treatment, 3 patterns of LN change were recorded: consistently shrinking LN (n = 33; 41.8%), inconsistently shrinking LN with temporary enlargement limited to the first week (n = 14; 17.7%), or also during the subsequent weeks (n = 32; 40.5%). Nodal density at planning is highly predictive of group assignment, with a larger mean density for consistently over inconsistently shrinking LNs (p = .009). Also, this grouping predicts the response at the end of treatment.
HPV-related LN behavior during IMRT is extremely variable but somewhat predictable on the basis of nodal density at planning.
volumetric change; lymph nodes; IMRT
Constitutive activation of nuclear factor κB (NF-κB) is associated with poor prognosis. Irinotecan demonstrates single-agent activity in head and neck cancer but activates NF-κB, promoting cell survival and resistance. Bortezomib is a proteasome inhibitor that inactivates NF-κB.
Patients and Methods
We performed a randomized phase II trial of bortezomib on days 1, 4, 8, and 11 and irinotecan on days 1 and 8 of each 21-day cycle or single-agent bortezomib on days 1, 4, 8, and 11 on a 21-day cycle. The addition of irinotecan to bortezomib was allowed in patients who progressed on bortezomib alone.
The response rate of bortezomib and irinotecan was 13%. One patient had a partial response to bortezomib alone (response rate 3%). No responses were seen in patients with addition of irinotecan at time of progression on bortezomib.
The bortezomib-based regimens evaluated in this study have minimal activity in recurrent or metastatic head and neck cancer.
head and neck cancer; chemotherapy; bortezomib; irinotecan; phase II
The epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) have been implicated as therapeutic targets for head and neck squamous cell carcinoma (HNSCC). Vandetanib is a small-molecule tyrosine kinase inhibitor (TKI) with dual specificity for EGFR and VEGFR. Here we characterize the phenotypic and biochemical effects of vandetanib on various HNSCC cell lines.
In vitro models were used for studying tumor cell viability, invasion, and signaling as well as in vivo xenograft models.
Treatment with vandetanib reduced viability, invasion, and tumor growth of HNSCC cell lines. Phosphorylation levels of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) were reduced in vandetanib-treated HNSCC cells. Additionally, vandetanib abrogates EGF-induced STAT3 activity and STAT3 target gene expression.
We demonstrated that vandetanib inhibits the growth of head and neck cancer cell lines. The antitumor effects of vandetanib appear to be exerted via the EGFR inhibitory effect of the compound.
vandetanib; HNSCC; EGFR; angiogenesis; molecular targeted therapy
A genome-wide association study for upper aerodigestive tract cancers identified 19 candidate single-nucleotide polymorphisms (SNPs). We used these SNPs to investigate the potential gene-gene and gene-environment interactions in head and neck squamous cell carcinoma (HNSCC) risk.
The 19 variants were genotyped using Taqman (Applied Biosystems) assays among 575 cases and 676 controls in our population-based case-control study.
A restricted cubic spline model suggested both ADH1B and HEL308 modified the association between smoking pack-years and HNSCC. Classification and regression tree analysis demonstrated a higher order interaction between smoking status, ADH1B, FLJ13089 and FLJ35784 in HNSCC risk. Compared with ever smokers carrying ADH1B T/C+T/T genotypes, smokers carrying ADH1B C/C genotype and FLJ13089 A/G+A/A genotypes had a highest risk of HNSCC (OR=1.84).
Our results suggest that the risk associated with these variants may be specifically important amongst specific exposure groups.
post-genome wide association study; head and neck cancer; gene and environment interaction
The significance of EGFR expression in advanced cutaneous squamous cell carcinoma (cSCC) of the head and neck remains poorly understood.
Retrospective review of patients with advanced stage (Stage III or IV) cSCC of the head and neck (n = 56).
The majority of patients (91%) had stage III disease, with 54% having regional metastasis and 9% with distant metastasis. Two-year survival was 64% and the 5-year survival was 56%. EGFR was found to be overexpressed in 56% of primary tumors and 58% of regional metastatic disease. Overall survival did not correlate with EGFR (p = 0.47) expression in primary lesions nor was it associated with an increase in regional (p = 0.74) or distant metastasis (p = 0.56). Furthermore, there was no correlation between clinicopathologic characteristics and EGFR expression
This data does not suggest upregulation of EGFR is associated with poor survival or aggressive disease.
Cutaneous squamous cell carcinoma; head and neck; survival; nonmelanoma skin cancer; epidermal growth factor receptor
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease usually diagnosed at late stage when cure rates are 40%. We examined a simple and inexpensive molecular tool that may aid HNSCC detection.
Building on prior findings that total protein levels are elevated in 102 HNSCC cases versus 84 controls, we further analyzed these levels with respect to important risk and demographic variables and compared results to solCD44. Using Multivariate Adaptive Regression Splines (MARS)-logit modeling and logistic regression, we determined whether total protein, solCD44 or the combination best identifies HNSCC.
Combined higher levels of solCD44 and protein were significantly associated with HNSCC (OR=24.90 95%CI 9.04, 68.57, AUC=0.786). A model including protein plus solCD44 resulted in a better area under the curve (0.796) than either marker alone.
Oral rinse levels of solCD44 and protein appear to hold promise for detection of HNSCC.
soluble CD44; ELISA assay; protein; head and neck squamous cell carcinoma; upper aerodigestive tract
Genetic variation in xenobiotic metabolizing enzymes may explain differing susceptibilities to the cancer causing effects of tobacco and alcohol.
We compared 203 oral squamous cell carcinoma cases and 416 controls for single nucleotide polymorphisms (SNPs) in 8 genes (CYP1A1, CYP2E1, MPO, mEH, GSTM1, GSTT1, GSTP1, and NAT2). Except for NAT2, genotype frequencies were similar in the 2 groups. We classified subjects as fast or slow NAT2 acetylators genotyping 13 NAT2 SNPs.
Fast acetylators were overrepresented in cases (53.7%) compared with controls (43.9%; odds ratio (OR) 1.55, 95% confidence interval (CI) 1.08–2.20; p value = .03). Gene–gene interaction testing suggested several cancer-NAT2 associations, with association strongest among persons without a CYP1A1 variant (*2C or *4) allele (OR 1.77, 95% CI 1.20–2.60, p value = .03) or with a variant MPO (463A) allele (OR 2.38, 95% CI 1.34–4.21, p value = .05).
These results implicate fast NAT2 acetylation as a risk factor for oral cancer.
tobacco; oral cancer; polymorphism; metabolizing enzymes; susceptibility
Patients with head and neck malignancies who have had solid organ transplant and require free tissue transfer are a unique population. This study was performed to evaluate the effect of immunosuppression on the rate of perioperative complications and the success of free tissue transfer in the head and neck.
Complications in solid organ transplant patients undergoing free tissue transfer for reconstruction of head and neck malignancies from 1998–2010 were evaluated.
A total of 22 flaps in 17 patients were performed. Eight patients (11/22 flaps) had complications. The median hospital stay was 6 days (range, 4–26 days). The median length of follow-up was 13.5 months (range, 3.5–49.9 months).
Solid organ transplant patients are at an increased risk of de novo malignancies due to chronic immunosuppression. This study demonstrates that free tissue transfer is a viable option in transplant patients with morbidity similar to nontransplant patients.
Free flap; free tissue transfer; head and neck reconstruction; organ transplant; immunosuppression
This study was to explore whether the efficacy of the EGFR tyrosine kinase inhibitor ZD1839 (Z, Iressa, gefitinib) plus chemotherapeutic agents docetaxel (D) and cisplatin (P) may benefit from sequencing of the combination.
Three head and neck cancer cell lines were used to study the effect of various combinations of and relative sequencing of D, P, and Z in cell growth inhibition. A population pharmacokinetic stimulation study was conducted on Z in silico, and used to together with the growth inhibition data to derive principles for future in vivo use of this drug combination.
The inhibitory effects of Z on combinations of D and P were sequence dependent. Treatment simultaneously with DPZ or with DP followed by Z (DP→Z) showed synergistic effects in all three cell lines. However, sequencing with Z followed by DP (Z→DP), gave an antagonistic effect, suggesting that D and P should be administered when the effect of Z is low. The induction of apoptosis was also sequence dependent. The in silico pharmacokinetic study suggested the feasibility of deriving a 5 day on 2 day off regimen for Z, in which D and P administration commences when levels of Z are low, allowing levels of Z to accumulate sufficiently during the remainder of the cycle.
These data suggests that it is feasible to design clinical trials with these settings to maximize the efficacy of this combined drug regimen.
EGFR; cytotoxic agent; docetaxel; cisplatin; apoptosis; head and neck cancer
We evaluated factors associated with long-term dependence on percutaneous endoscopic gastrostomy (PEG) tubes.
154 patients receiving treatment at the University of Alabama at Birmingham between 2002 and 2004 who underwent PEG tube placement were identified through retrospective review of medical records. Using binary logistic regression, we evaluated the association of various factors on long-term dependence on PEG tubes.
25.3% of survivors remained PEG tube dependent at 12 months. The odds of long-term PEG-tube dependence were greater for those who did not have partners compared with those who had partners (OR 3.33, p=0.004), for patients who received radiation therapy (OR 6.21, p=0.018), and for those who had a tracheotomy in place for longer than thirty days (OR 4.328, p=0.035).
Data suggest that interventions targeted at reducing long-term dependence on PEG tubes take into account not only treatment-related factors, but also the important role that social support plays.
Gastrostomy Tubes; Head and Neck Cancer; Long-term PEG Dependence; Survivors; Social Support