Human Papillomavirus-positive Squamous Cell Carcinoma Research Articles

Adjuvant Treatment Deintensification after Transoral Surgery for Human Papillomavirus-Positive Squamous Cell Carcinoma of the Oropharynx

Adjuvant Treatment Deintensification after Transoral Surgery for Human Papillomavirus-Positive Squamous Cell Carcinoma of the Oropharynx

Intrathyroidal metastasis of tonsillar squamous cell carcinoma masquerading as a primary thyroid tumor.

Intrathyroidal metastasis of tonsillar squamous cell carcinoma is rare. To date, only six cases have been reported in the literature. This case was unusual and presented with thyromegaly before the diagnosis of the primary tumor. A 55-year-old male patient was suspected to have a primary thyroid tumor with nodal metastasis. The thyroid gland was diffusely enlarged, with no discernible mass. Histologically, the thyroid parenchyma revealed extensive endolymphatic tumor emboli, which were positive for p40 and p16 in a background of chronic lymphocytic thyroiditis. Positron emission tomography-computed tomography revealed hypermetabolic activity in the right tonsillar region. Tonsillar biopsy revealed human papillomavirus-positive squamous cell carcinoma. The present case is the first reported case of intrathyroidal metastasis of tonsillar squamous cell carcinoma with an initial clinical presentation of thyroid enlargement before the primary tumor of tonsillar cancer was diagnosed.

A Lack of Effectiveness in the ATM-Orchestrated DNA Damage Response Contributes to the DNA Repair Defect of HPV-Positive Head and Neck Cancer Cells.

Patients with human papillomavirus-positive squamous cell carcinoma of the head and neck (HPV+ HNSCC) have a favorable prognosis compared to those with HPV-negative (HPV−) ones. We have shown previously that HPV+ HNSCC cell lines are characterized by enhanced radiation sensitivity and impaired DNA double-strand break (DSB) repair. Since then, various publications have suggested a defect in homologous recombination (HR) and dysregulated expression of DSB repair proteins as underlying mechanisms, but conclusions were often based on very few cell lines. When comparing the expression levels of suggested proteins and other key repair factors in 6 HPV+ vs. 5 HPV− HNSCC strains, we could not confirm most of the published differences. Furthermore, HPV+ HNSCC strains did not demonstrate enhanced sensitivity towards PARP inhibition, questioning a general HR defect. Interestingly, our expression screen revealed minimal levels of the central DNA damage response kinase ATM in the two most radiosensitive HPV+ strains. We therefore tested whether insufficient ATM activity may contribute to the enhanced cellular radiosensitivity. Irrespective of their ATM expression level, radiosensitive HPV+ HNSCC cells displayed DSB repair kinetics similar to ATM-deficient cells. Upon ATM inhibition, HPV+ cell lines showed only a marginal increase in residual radiation-induced γH2AX foci and induction of G2 cell cycle arrest as compared to HPV− ones. In line with these observations, ATM inhibition sensitized HPV+ HNSCC strains less towards radiation than HPV− strains, resulting in similar levels of sensitivity. Unexpectedly, assessment of the phosphorylation kinetics of the ATM targets KAP-1 and Chk2 as well as ATM autophosphorylation after radiation did not indicate directly compromised ATM activity in HPV-positive cells. Furthermore, ATM inhibition delayed radiation induced DNA end resection in both HPV+ and HPV− cells to a similar extent, further suggesting comparable functionality. In conclusion, DNA repair kinetics and a reduced effectiveness of ATM inhibition clearly point to an impaired ATM-orchestrated DNA damage response in HPV+ HNSCC cells, but since ATM itself is apparently functional, the molecular mechanisms need to be further explored.

Metabolic Plasticity and Combinatorial Radiosensitisation Strategies in Human Papillomavirus-Positive Squamous Cell Carcinoma of the Head and Neck Cell Lines.

Simple SummaryA subset of head and neck cancers (SCCHN) are caused by human papillomavirus (HPV). As these tumours tend to affect younger patients and are associated with favourable survival, there is a pressing need to find ways to reduce long-term treatment toxicity while maintaining oncological efficacy. We studied utilisation of metabolic pathways in HPV-positive SCCHN cells with the aim of exploiting such for potential therapeutic benefit. We found that these tumours maintained metabolic diversity, in contrast to what we have observed in traditional SCCHN cells associated with mutations in the TP53 gene. This, in turn, correlated with susceptibility to metabolic inhibitors, insofar as a combination of these agents acting on different metabolic pathways was required to augment the effects of ionising radiation (a mainstay of treatment for SCCHN). Notionally, this may provide a means of treatment de-intensification by facilitating radiation dose reduction to minimise the impact of treatment on long-term function.Background: A major objective in the management of human papillomavirus (HPV)-positive squamous cell carcinoma of the head and neck (SCCHN) is to reduce long-term functional ramifications while maintaining oncological outcomes. This study examined the metabolic profile of HPV-positive SCCHN and the potential role of anti-metabolic therapeutics to achieve radiosensitisation as a potential means to de-escalate radiation therapy. Methods: Three established HPV-positive SCCHN cell lines were studied (UM-SCC-104, UPCI:SCC154, and VU-SCC-147), together with a typical TP53 mutant HPV-negative SCCHN cell line (UM-SCC-81B) for comparison. Metabolic profiling was performed using extracellular flux analysis during specifically designed mitochondrial and glycolytic stress tests. Sensitivity to ionising radiation (IR) was evaluated using clonogenic assays following no treatment, or treatment with: 25 mM 2-deoxy-D-glucose (glycolytic inhibitor) alone; 20 mM metformin (electron transport chain inhibitor) alone; or 25 mM 2-deoxy-D-glucose and 20 mM metformin combined. Expression levels of p53 and reporters of p53 function (MDM2, p53, Phospho-p53 [Ser15], TIGAR and p21 [CDKN1A]) were examined by western blotting. Results: HPV-positive SCCHN cell lines exhibited a diverse metabolic phenotype, displaying robust mitochondrial and glycolytic reserve capacities. This metabolic profile, in turn, correlated with IR response following administration of anti-metabolic agents, in that both 2-deoxy-D-glucose and metformin were required to significantly potentiate the effects of IR in these cell lines. Conclusions: In contrast to our recently published data on HPV-negative SCCHN cells, which display relative glycolytic dependence, HPV-positive SCCHN cells can only be sensitised to IR using a complex anti-metabolic approach targeting both mitochondrial respiration and glycolysis, reflecting their metabolically diverse phenotype. Notionally, this may provide an attractive platform for treatment de-intensification in the clinical setting by facilitating IR dose reduction to minimise the impact of treatment on long-term function.

P-13 Metabolism and Anti-Metabolic Therapeutic Strategies in Human Papillomavirus-Positive Squamous Cell Carcinoma of the Head and Neck

P-13 Metabolism and Anti-Metabolic Therapeutic Strategies in Human Papillomavirus-Positive Squamous Cell Carcinoma of the Head and Neck

Modern perspectives of oral squamous cell carcinoma

The article is devoted to the modern perspectives of the etiology, pathogenesis, diagnosis and prognostic factors in theoral squamous cell carcinoma. In the new edition of the WHO Classification of Head and Neck Tumors of 2017, the concept of potentially malignant diseases is introduced, which include erythroplakia, leukoplakia, oral submucous fibrosis, dyskeratosiscongenita, smokeless tobacco keratosis, palatallesions associated with reverse smoking, chronic candidiasis, lichen planus, discoid lupus erythematosus, syphilitic glossitis and actinic keratosis (liponly). A binary system for assessing oral epithelial dysplasia assessing is proposed. In Chapter 5, a separation of squamous cell carcinoma with a positive and negative reaction to human papillomavirus (HPV) is performed. It has been shown that patients with HPV positive squamous cell carcinoma have a better prognosis of the disease, which confirms the clinical distinction between oropharyngeal tumors and oral mucosa.

The Clinical Significance of Neuroendocrine Marker Expression in Human Papillomavirus–Positive Squamous Cell Carcinoma of Head and Neck Origin

The Clinical Significance of Neuroendocrine Marker Expression in Human Papillomavirus–Positive Squamous Cell Carcinoma of Head and Neck Origin

Concurrent Human Papillomavirus-Positive Squamous Cell Carcinoma of the Oropharynx in a Married Couple.

Background. Although alcohol and tobacco use are known risk factors for development of squamous cell carcinoma in the head and neck, human papillomavirus (HPV) has been increasingly associated with this group of cancers. We describe the case of a married couple who presented with HPV-positive oropharynx squamous cell carcinoma within two months of each other. Methods. Tumor biopsies were positive for p16 and high-risk HPV in both patients. Sanger sequencing showed a nearly identical HPV16 strain in both patients. Both patients received chemoradiation, and one patient also underwent transoral robotic tongue base resection with bilateral neck dissection. Results. Both patients showed no evidence of recurrent disease on follow-up PET imaging. Conclusions. New head and neck symptoms should be promptly evaluated in the partner of a patient with known HPV-positive oropharynx cancer. This case expands the limited current literature on concurrent presentation of HPV-positive oropharynx squamous cell carcinoma in couples.

Clinical outcomes in elderly patients with human papillomavirus-positive squamous cell carcinoma of the oropharynx treated with definitive chemoradiation therapy.

The benefit of combined chemoradiation in elderly patients with human papillomavirus (HPV)-positive locally advanced oropharyngeal squamous cell carcinoma (SCC) must be balanced with the potential for higher toxicity rates. We performed a retrospective review of our institutional experience. Patients 70 years or older with p16-positive oropharyngeal SCC treated with definitive chemoradiation from 2005 to 2013 were evaluated. Overall survival (OS), disease-free survival (DFS), and locoregional failure-free survival were calculated. Twenty-one eligible patients had a follow-up of 22.4 months. Estimated 5-year OS, DFS, and locoregional failure-free survival were 76.0%, 40%, and 95%, respectively. There was 1 death from acute toxicity, and 50% had unplanned hospitalizations. Sixty percent had late toxicity, and 6-month feeding tube dependence was 25%. Elderly patients with HPV-positive locally advanced SCC of the oropharynx treated with definitive chemoradiation had good OS but high rates of acute and long-term toxicity. © 2015 Wiley Periodicals, Inc. Head Neck 38: 846-851, 2015.

Transoral anatomy of the tonsillar fossa and lateral pharyngeal wall: Anatomic dissection with radiographic and clinical correlation

To evaluate the transoral anatomy of the tonsillar fossa and lateral pharyngeal wall and to correlate these findings with radiographic measurements and transoral robotic surgery (TORS) of patients with early tonsillar tumor. Preclinical cadaveric study and patient cohort. Six complete cadaveric dissections were performed to identify key anatomic landmarks, and these landmarks were validated in two consecutive patients with T1 human papillomavirus-positive squamous cell carcinoma of the tonsil treated by TORS. For radiographic landmark analysis, 25 patients who underwent contrast-enhanced computed tomography (CT) of the neck for a variety of endoscopic skull base procedures were selected. Measurements were taken from the lateral pharyngeal wall at C2-C3 interspace and greater horn of hyoid (C6) to the external carotid artery (ECA). The glossopharyngeal (IX) nerve was consistently identified deep to the superior constrictor musculature and at the intersection of the posterior tonsillar pillar with the base of tongue. The styloglossus muscle forms the deep plane medial to the ECA. The mean measurements for left C2-C3 interspace to the ECA and right C2-C3 interspace to ECA were 17.6 ± 0.8 mm and 18.4 ± 0.8 mm, respectively. Similarly, the mean measurements for left hyoid to ECA and right hyoid to ECA were 3.4 ± 0.8 mm and 4.3 ± 0.6 mm, respectively. A systematic approach to dissect the tonsillar fossa and lateral pharyngeal wall can be performed using key anatomic landmarks. CT measurements taken at the C2-C3 interspace and greater horn of hyoid bone (C6 level) to the ECA are consistently and reliably achieved.

HPV Positive Squamous Cell Carcinoma of the Oropharynx. Are we Observing an Unusual Pattern of Metastases?

To describe the clinical, histopathologic, immunohistochemical and molecular features of human papilloma virus (HPV)+ squamous cell carcinomas of the oropharynx that had an atypical clinical course. Four patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) were identified retrospectively based on unanticipated clinical behavior. The histopathology, immunohistochemistry and molecular studies of both the primary tumor and the metastases were analyzed to look for any predictors to explain the clinical course. The four patients were all male (average age 55) who presented initially with a neck mass and had stage IVA disease. Three of the primary tumors were nonkeratinizing squamous cell carcinoma and one case was a hybrid tumor of both high-grade squamous cell carcinoma and nonkeratinizing type, and all were p16 and HPV 16/18 positive. All patients received concurrent chemoradiation as primary therapy and had a complete response. Disease-free survival ranged from 7 to 15 months and metastases in 3 patients occurred only in bone, including the sternum, humerus, clavicle, and vertebrae. In one patient, distant metastases were identified in the pancreas, liver, lung and skull base. All metastatic lesions were nonkeratinizing morphology and were p16 and/or HPV positive. Two patients died of their disease, one patient is alive with disease and one patient is disease-free. Although infrequent, unanticipated clinical outcomes can occur in HPV-related OPSCC including distant metastases and bone-only metastases. The tumor morphology of the metastases was comparable to the primary and retained p16 and HPV expression.

Reduced apoptotic levels in squamous but not basal cell carcinomas correlates with detection of cutaneous human papillomavirus.

We have investigated the apoptotic levels and expression of the apoptotic inducer Bak in non-melanoma skin cancers. Squamous cell carcinomas of known human papillomavirus status from immunocompetent patients were analysed for the expression of the Bak protein, and the expression profile was compared both to the presence of apoptotic cells and the proliferation marker Ki-67. We demonstrate an inverse correlation between human papillomavirus positivity and Bak expression in squamous cell carcinomas, with concomitantly fewer apoptoic cells being detected in the human papillomavirus positive tumours. Bak expression was not observed in basal cell carcinomas irrespective of human papillomavirus status, suggesting that Bak only plays a role in signalling apoptosis in squamous, but not basal, cell cancers. No differences were observed in the proliferation rates between papillomavirus positive and negative squamous cell tumours. However, a significant decrease in the number of apoptotic cells was observed in human papillomavirus-positive squamous cell carcinomas which suggests that the virus may have significantly altered the relationship between proliferation and apoptosis in a proportion of these tumours.British Journal of Cancer (2002) 87, 319–323. doi:10.1038/sj.bjc.6600431 www.bjcancer.com© 2002 Cancer Research UK