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Loth AG, Wild PJ. [Individualization and standardization in head and neck pathology]. HNO 2025:10.1007/s00106-025-01627-y. [PMID: 40237827 DOI: 10.1007/s00106-025-01627-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2025] [Indexed: 04/18/2025]
Abstract
Individualization and standardization are seemingly contradictory requirements in medicine. In the treatment of head and neck cancer, both terms have a direct influence on diagnostic procedures, which are usually carried out in pathology institutes. The current article examines the conflicting requirements arising from various technical analyses, regulatory requirements, structural changes due to digitalization, and the advent of personalized medicine. On the one hand, the goal is to promote interdisciplinary exchange by understanding the challenges and, on the other, to provide the otorhinolaryngologist with a practical understanding of the common and current pathological diagnostic tests. Using pathology as an example, it can be shown that standardization of procedures ultimately serves to improve individualized treatment. At the same time, however, the following challenges are also apparent: despite comprehensive regulations and a laboratory environment with digital support, standardization is very time consuming and costly. If similar standardization approaches are to be implemented in an operative environment such as, e.g., ENT surgery, the effort involved can be expected to be equivalent or higher due to the human factor.
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Affiliation(s)
- Andreas G Loth
- Universitätsklinikum Frankfurt, Klinik für Hals‑, Nasen- und Ohrenheilkunde, Goethe-Universität Frankfurt, Theodor-Stern-Kai 7, 60450, Frankfurt am Main, Deutschland.
| | - Peter J Wild
- Universitätsklinikum Frankfurt, Dr. Senckenbergisches Institut für Pathologie und Humangenetik, Goethe-Universität Frankfurt, Frankfurt am Main, Deutschland
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Ren Y, Xiong W, Feng C, Yu D, Wang X, Yang Q, Yu S, Zhang H, Huo B, Jiang H, Li Z, Wang J, Su YX, Yang P, Liao Y, Zhong Q, Wang J. Multi-omics insights into the molecular signature and prognosis of hypopharyngeal squamous cell carcinoma. Commun Biol 2025; 8:370. [PMID: 40044946 PMCID: PMC11882983 DOI: 10.1038/s42003-025-07700-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Accepted: 02/07/2025] [Indexed: 03/09/2025] Open
Abstract
Approximately two-thirds of hypopharyngeal squamous cell carcinoma (HPSCC) cases are diagnosed at advanced stages, with the worst prognosis among head and neck squamous cell carcinomas (HNSCCs). Identifying biomarkers for high-risk patients requiring aggressive treatment is crucial. We present mutational, transcriptomic, and proteomic studies of 103 Chinese HPSCC patients and observe a higher prevalence and poorer prognosis in males. Estrogen response pathways are up-regulated, and proteins phosphorylated by protein kinase C (PKC) and cyclin-dependent kinases (CDKs) are aberrantly regulated in HPSCC. We identify aberrant copy number regions including SOX2(3q26.33), FGFR(8p11.23), CCND1(11q13.3), CDKN2A/2B(9p21.3), and MYC(8q24.21). Human papillomavirus (HPV) status combined with highly mutated genes, such as SYNE1 in HPV(-) and MUC4 in HPV(+) patients, were assessed as prognosis markers. A predictive model involving clinical factors and expression of six genes was established and cross-site validated. These findings open new opportunities for stratifying high-risk patients and molecular targets for personalized therapeutic strategies.
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Affiliation(s)
- Yanxin Ren
- Department of Head and Neck Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wei Xiong
- Department of Radiotherapy, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chun Feng
- Department of Otolaryngology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Dan Yu
- Division of Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, the University of Hong Kong, Hong Kong SAR, China
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China
| | - Xiaoyan Wang
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Qing Yang
- Department of Head and Neck Surgery, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Siting Yu
- Department of Radiotherapy, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Hongjiang Zhang
- Department of Radiotherapy, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Bangyun Huo
- Department of Otolaryngology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Honglu Jiang
- Department of Otolaryngology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China
| | - Zuli Li
- Institute for Viral Hepatitis & Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology of Infectious Diseases, MOE (Ministry of Education), Chongqing, China
| | - Junlin Wang
- Division of Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, the University of Hong Kong, Hong Kong SAR, China
- Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, the University of Hong Kong, Hong Kong SAR, China
| | - Yu-Xiong Su
- Division of Oral and Maxillofacial Surgery, Faculty of Dentistry, the University of Hong Kong, Hong Kong SAR, China
| | - Ping Yang
- Department of Quantitative Health Science, Mayo Clinic, Scottsdale, USA
| | - Yong Liao
- Institute for Viral Hepatitis & Department of Infectious Diseases, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- Key Laboratory of Molecular Biology of Infectious Diseases, MOE (Ministry of Education), Chongqing, China
| | - Qi Zhong
- Department of Otolaryngology Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China.
| | - Junwen Wang
- Division of Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, the University of Hong Kong, Hong Kong SAR, China.
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong SAR, China.
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Verhees F, Demers I, Legemaate D, Jacobs R, Hoeben A, Kremer B, Speel EJ. Exploring the antiproliferative effect of PI3K/Akt/mTOR pathway and CDK4/6 inhibitors in human papillomavirus‑positive and ‑negative head and neck squamous cell carcinoma cell lines. Int J Oncol 2025; 66:13. [PMID: 39791215 PMCID: PMC11753768 DOI: 10.3892/ijo.2025.5719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 09/30/2024] [Indexed: 01/12/2025] Open
Abstract
Human papillomavirus (HPV)‑positive and -negative head and neck squamous cell carcinoma (HNSCC) are often associated with activation of the phosphatidylinositol 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway due to mutations or amplifications in PI3KCA, loss of PTEN or activation of receptor tyrosine kinases. In HPV‑negative tumors, CDKN2A (encoding p16 protein) inactivation or CCND1 (encoding Cyclin D1 protein) amplification frequently results in sustained cyclin‑dependent kinase (CDK) 4/6 activation. The present study aimed to investigate the efficacy of the CDK4/6 inhibitors (CDKi) palbociclib and ribociclib, and the PI3K/Akt/mTOR pathway inhibitors (PI3Ki) gedatolisib, buparlisib and alpelisib, in suppressing cell viability of HPV‑positive and ‑negative HNSCC cell lines. Inhibitor efficacy was assessed in vitro using MTT assay and western blotting analysis. Cell cycle analysis was performed using flow cytometry and apoptosis was assessed using annexin V staining. Metabolic changes in terms of glycolysis and oxidative metabolism were measured by Seahorse XF96 extracellular Flux analysis. The results of the present study showed that both HPV‑positive and ‑negative HNSCC cell lines were sensitive to PI3Ki. In general, PI3Ki decreased PI3K/Akt/mTOR pathway activity, resulting in apoptosis, and decreased oxidative and glycolytic metabolism. The CDKi were particularly effective in blocking HPV‑negative cell line viability, showing decreased retinoblastoma expression and G1‑phase cell cycle arrest, whereas apoptosis was not induced. Thus, PI3Ki and CDKi efficiently inhibited their respective pathways and HNSCC cell viability in vitro, with the latter occurring only in HPV‑negative cell lines. Whereas PI3Ki induced apoptosis and attenuated cellular metabolism, CDKi led to cell cycle arrest. Further research should be performed to elucidate whether (a combination of) these inhibitors may be effective therapeutic agents for patients with HNSCC.
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Affiliation(s)
- Femke Verhees
- Department of Otorhinolaryngology, Head and Neck Surgery, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
| | - Imke Demers
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
| | - Dion Legemaate
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
| | - Robin Jacobs
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
| | - Ann Hoeben
- Department of Medical Oncology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
| | - Bernd Kremer
- Department of Otorhinolaryngology, Head and Neck Surgery, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
| | - Ernst-Jan Speel
- Department of Pathology, GROW Research Institute for Oncology and Reproduction, Maastricht University Medical Center, 6229HX Maastricht, The Netherlands
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James CD, Otoa RO, Youssef AH, Fontan CT, Sannigrahi MK, Windle B, Basu D, Morgan IM. HPV16 genome structure analysis in oropharyngeal cancer PDXs identifies tumors with integrated and episomal genomes. Tumour Virus Res 2024; 18:200285. [PMID: 38936774 PMCID: PMC11261002 DOI: 10.1016/j.tvr.2024.200285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/26/2024] [Accepted: 06/11/2024] [Indexed: 06/29/2024] Open
Abstract
HPV + oropharyngeal squamous cell carcinoma (OPC) incidence recently surpassed cervical cancer and is the most common HPV-related cancer in the developed world. HPV16 is in ∼90 % of HPV + OPCs, with episomal genomes in the majority of cases. Most existing HPV16+ cancer cell lines derive from outside the oropharynx and harbor integrated HPV genomes. Thus, there is need for OPC preclinical models to evaluate standard and experimental therapeutics in the presence of episomal HPV16 oncogenic drivers. Here we characterize HPV genome structures in eight HPV16+ OPC patient-derived xenografts (PDXs), and evaluate their responses to standard chemotherapy. HPV genome state was investigated by combining Southern blot, T5 exonuclease assay, whole genome sequencing, and RNAseq data. This analysis revealed complexity and variation in integrated vs. episomal HPV forms across PDXs and demonstrated that four PDXs predominantly contain episomal HPV16. Episomal status did not ensure favorable in vivo responses to cisplatin therapy, despite the more favorable prognosis previously attributed to episomal HPV + tumors; this could be due to the small number present in the dataset. Our analysis establishes PDX models as test platforms for novel therapies designed to target maintenance of the episomal forms of HPV16 that commonly appear in OPC.
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Affiliation(s)
- Claire D James
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Raymonde O Otoa
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Aya H Youssef
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Christian T Fontan
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA
| | - Malay K Sannigrahi
- Dept. Otorhinolaryngology-Head and Neck Surgery, The University of Pennsylvania, Philadelphia, PA, USA
| | - Brad Windle
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA; VCU Massey Cancer Center, Richmond, VA, 23298, USA
| | - Devraj Basu
- Dept. Otorhinolaryngology-Head and Neck Surgery, The University of Pennsylvania, Philadelphia, PA, USA.
| | - Iain M Morgan
- Virginia Commonwealth University (VCU), Philips Institute for Oral Health Research, School of Dentistry, Richmond, VA, 23298, USA; VCU Massey Cancer Center, Richmond, VA, 23298, USA.
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Zupancic M, Kostopoulou ON, Holzhauser S, Lukoseviciute M, Jylhä C, Marklund L, Näsman A, Sivars L, Dalianis T. Human papillomavirus (HPV) load is higher in HPVDNA/p16 positive than in HPVDNA positive/p16 negative oropharyngeal squamous cell carcinoma but does not differ significantly between various subsites or correlate to survival. Oral Oncol 2024; 151:106749. [PMID: 38461771 DOI: 10.1016/j.oraloncology.2024.106749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 02/26/2024] [Accepted: 03/06/2024] [Indexed: 03/12/2024]
Abstract
OBJECTIVE Patients with human papillomavirus DNA positive (HPVDNA+) and p16ink4a overexpressing (p16+) oropharyngeal squamous cell carcinoma (OPSCC), especially those with cancer in the tonsillar and base of tongue subsites as compared to other OPSCC subsites have a better outcome than those with only HPVDNA+ or only p16+ cancer. Likewise having a high viral load has been suggested to be a positive prognostic factor. We therefore hypothesized, that HPV viral load could vary depending on OPSCC subsite, as well as with regard to whether the cancer was HPVDNA+ and p16+, or only HPVDNA+, or only p16+ and that this affected outcome. MATERIAL AND METHODS To address these issues HPV viral load was determined by HPV digital droplet (dd) PCR in tumor biopsies with previously known HPVDNA/p16 status from 270 OPSCC patients diagnosed 2000-2016 in Stockholm, Sweden. More specifically, of these patients 235 had HPVDNA+/p16+, 10 had HPVDNA+/p16-, 13 had HPVDNA-/p16+ and 12 had HPVDNA-/p16- cancer. RESULTS We found that HPVDNA+/p16+ OPSCC had a significantly higher viral load than HPVDNA+/p16- OPSCC. Moreover, there was a tendency for a higher viral load in the tonsillar and base of tongue OPSCC subsites compared to the other subsites and for a low viral load to correlate to a better clinical outcome but none of these tendencies reached statistical significance. CONCLUSION To conclude, the mean viral load in HPVDNA+/p16+ OPSCC was higher than in HPVDNA+/p16- OPSCC, but there was no statistically significant difference in viral load depending on OPSCC subsite or on clinical outcome.
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Affiliation(s)
- Mark Zupancic
- Dept. of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Medical Unit Head, Neck, Lung, and Skin Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden
| | | | - Stefan Holzhauser
- Dept. of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | | | - Cecilia Jylhä
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Dept of Clinical Genetics, Karolinska University Hospital, 171 76 Stockholm, Sweden
| | - Linda Marklund
- Medical Unit Head, Neck, Lung, and Skin Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden; Department of Clinical Sciences, Intervention and Technology, Division of ENT Diseases, Karolinska Institutet, Sweden; Department of Surgical Sciences, Section of Otolaryngology and Head and Neck Surgery, Uppsala University, Uppsala, Sweden
| | - Anders Näsman
- Dept. of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Dept of Clinical Pathology, Karolinska University Hospital, Stockholm, Sweden
| | - Lars Sivars
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Tina Dalianis
- Dept. of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden; Medical Unit Head, Neck, Lung, and Skin Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.
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Rao A, Ni Z, Suresh D, Mohanty C, Wang AR, Lee DL, Nickel KP, Varambally SRJ, Lambert PF, Kendziorski C, Iyer G. Targeted inhibition of BET proteins in HPV-16 associated head and neck squamous cell carcinoma reveals heterogeneous transcription response. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.02.560587. [PMID: 37873389 PMCID: PMC10592929 DOI: 10.1101/2023.10.02.560587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Integrated human papillomavirus (HPV-16) associated head and neck squamous cell carcinoma (HNSCC) tumors have worse survival outcomes compared to episomal HPV-16 HNSCC tumors. Therefore, there is a need to differentiate treatment for HPV-16 integrated HNSCC from other viral forms. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. However, the mechanism of BET protein-mediated transcription of viral-cellular genes in the integrated viral-HNSCC genomes needs to be better understood. We show that BET inhibition downregulates E6 significantly independent of the viral transcription factor, E2, and there was overall heterogeneity in the downregulation of viral transcription in response to the effects of BET inhibition across HPV-associated cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4 and mirrored downregulation of viral E6 and E7 expression. Strikingly, there was heterogeneity in the reactivation of p53 levels despite E6 downregulation, while E7 downregulation did not alter Rb levels significantly. We identified that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A expression. Overall, our studies show that BET inhibition provokes a G1-cell cycle arrest with apoptotic activity and suggests that BET inhibition regulates both viral and cellular gene expression in HPV-associated HNSCC.
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Affiliation(s)
- Aakarsha Rao
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
| | - Zijian Ni
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Dhruthi Suresh
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
| | - Chitrasen Mohanty
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Albert R. Wang
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, 53705, USA
| | - Denis L Lee
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, Madison, 53705, WI, USA
| | - Kwangok P. Nickel
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
| | - Sooryanarayana Randall J. Varambally
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA
| | - Paul F. Lambert
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
- University of Wisconsin Carbone Cancer Center, Madison, 53705, WI, USA
| | - Christina Kendziorski
- Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, 53706, USA
| | - Gopal Iyer
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
- McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA
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Goričan L, Büdefeld T, Čelešnik H, Švagan M, Lanišnik B, Potočnik U. Gene Expression Profiles of Methyltransferases and Demethylases Associated with Metastasis, Tumor Invasion, CpG73 Methylation, and HPV Status in Head and Neck Squamous Cell Carcinoma. Curr Issues Mol Biol 2023; 45:4632-4646. [PMID: 37367043 DOI: 10.3390/cimb45060294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/12/2023] [Accepted: 05/25/2023] [Indexed: 06/28/2023] Open
Abstract
Epigenetic studies on the role of DNA-modifying enzymes in HNSCC tumorigenesis have focused on a single enzyme or a group of enzymes. To acquire a more comprehensive insight into the expression profile of methyltransferases and demethylases, in the present study, we examined the mRNA expression of the DNA methyltransferases DNMT1, DNMT3A, and DNMT3B, the DNA demethylases TET1, TET2, TET3, and TDG, and the RNA methyltransferase TRDMT1 by RT-qPCR in paired tumor-normal tissue samples from HNSCC patients. We characterized their expression patterns in relation to regional lymph node metastasis, invasion, HPV16 infection, and CpG73 methylation. Here, we show that tumors with regional lymph node metastases (pN+) exhibited decreased expression of DNMT1, 3A and 3B, and TET1 and 3 compared to non-metastatic tumors (pN0), suggesting that metastasis requires a distinct expression profile of DNA methyltransferases/demethylases in solid tumors. Furthermore, we identified the effect of perivascular invasion and HPV16 on DNMT3B expression in HNSCC. Finally, the expression of TET2 and TDG was inversely correlated with the hypermethylation of CpG73, which has previously been associated with poorer survival in HNSCC. Our study further confirms the importance of DNA methyltransferases and demethylases as potential prognostic biomarkers as well as molecular therapeutic targets for HNSCC.
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Affiliation(s)
- Larisa Goričan
- Centre for Human Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
| | - Tomaž Büdefeld
- Centre for Human Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
| | - Helena Čelešnik
- Centre for Human Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
- Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, 2000 Maribor, Slovenia
| | - Matija Švagan
- Department of Otorhinolaryngology, Cervical and Maxillofacial Surgery, University Medical Centre Maribor, Ljubljanska ulica 5, 2000 Maribor, Slovenia
| | - Boštjan Lanišnik
- Department of Otorhinolaryngology, Cervical and Maxillofacial Surgery, University Medical Centre Maribor, Ljubljanska ulica 5, 2000 Maribor, Slovenia
| | - Uroš Potočnik
- Centre for Human Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, 2000 Maribor, Slovenia
- Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, 2000 Maribor, Slovenia
- Department for Science and Research, University Medical Centre Maribor, 2000 Maribor, Slovenia
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Haist M, Kaufmann J, Kur IM, Zimmer S, Grabbe S, Schmidberger H, Weigert A, Mayer A. Response to primary chemoradiotherapy of locally advanced oropharyngeal carcinoma is determined by the degree of cytotoxic T cell infiltration within tumor cell aggregates. Front Immunol 2023; 14:1070203. [PMID: 37187729 PMCID: PMC10175951 DOI: 10.3389/fimmu.2023.1070203] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 04/13/2023] [Indexed: 05/17/2023] Open
Abstract
Background Effective anti-tumor immune responses are mediated by T cells and require organized, spatially coordinated interactions within the tumor microenvironment (TME). Understanding coordinated T-cell-behavior and deciphering mechanisms of radiotherapy resistance mediated by tumor stem cells will advance risk stratification of oropharyngeal cancer (OPSCC) patients treated with primary chemoradiotherapy (RCTx). Methods To determine the role of CD8 T cells (CTL) and tumor stem cells for response to RCTx, we employed multiplex immunofluorescence stains on pre-treatment biopsy specimens from 86 advanced OPSCC patients and correlated these quantitative data with clinical parameters. Multiplex stains were analyzed at the single-cell level using QuPath and spatial coordination of immune cells within the TME was explored using the R-package Spatstat. Results Our observations demonstrate that a strong CTL-infiltration into the epithelial tumor compartment (HR for overall survival, OS: 0.35; p<0.001) and the expression of PD-L1 on CTL (HR: 0.36; p<0.001) were both associated with a significantly better response and survival upon RCTx. As expected, p16 expression was a strong predictor of improved OS (HR: 0.38; p=0.002) and correlated with overall CTL infiltration (r: 0.358, p<0.001). By contrast, tumor cell proliferative activity, expression of the tumor stem cell marker CD271 and overall CTL infiltration, regardless of the affected compartment, were not associated with response or survival. Conclusion In this study, we could demonstrate the clinical relevance of the spatial organization and the phenotype of CD8 T cells within the TME. In particular, we found that the infiltration of CD8 T cells specifically into the tumor cell compartment was an independent predictive marker for response to chemoradiotherapy, which was strongly associated with p16 expression. Meanwhile, tumor cell proliferation and the expression of stem cell markers showed no independent prognostic effect for patients with primary RCTx and thus requires further study.
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Affiliation(s)
- Maximilian Haist
- Department of Dermatology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States
- Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA, United States
- *Correspondence: Maximilian Haist,
| | - Justus Kaufmann
- Department of Radiation Oncology and Radiotherapy, University Medical Center, Mainz, Germany
| | - Ivan-Maximiliano Kur
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Stefanie Zimmer
- Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Stephan Grabbe
- Department of Dermatology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany
| | - Heinz Schmidberger
- Department of Radiation Oncology and Radiotherapy, University Medical Center, Mainz, Germany
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - Arnulf Mayer
- Institute of Pathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
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Ward BJH, Schaal DL, Nkadi EH, Scott RS. EBV Association with Lymphomas and Carcinomas in the Oral Compartment. Viruses 2022; 14:2700. [PMID: 36560704 PMCID: PMC9783324 DOI: 10.3390/v14122700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/21/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Epstein-Barr virus (EBV) is an oncogenic human herpesvirus infecting approximately 90% of the world's population. The oral cavity serves a central role in the life cycle, transmission, and pathogenesis of EBV. Transmitted to a new host via saliva, EBV circulates between cellular compartments within oral lymphoid tissues. Epithelial cells primarily support productive viral replication, while B lymphocytes support viral latency and reactivation. EBV infections are typically asymptomatic and benign; however, the latent virus is associated with multiple lymphomas and carcinomas arising in the oral cavity. EBV association with cancer is complex as histologically similar cancers often test negative for the virus. However, the presence of EBV is associated with distinct features in certain cancers. The intrinsic ability of EBV to immortalize B-lymphocytes, via manipulation of survival and growth signaling, further implicates the virus as an oncogenic cofactor. A distinct mutational profile and burden have been observed in EBV-positive compared to EBV-negative tumors, suggesting that viral infection can drive alternative pathways that converge on oncogenesis. Taken together, EBV is also an important prognostic biomarker that can direct alternative therapeutic approaches. Here, we discuss the prevalence of EBV in oral malignancies and the EBV-dependent mechanisms associated with tumorigenesis.
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Affiliation(s)
| | | | | | - Rona S. Scott
- Department of Microbiology and Immunology, Center for Applied Immunology and Pathological Processes, Feist-Weiller Cancer Center, Louisiana State University Health-Shreveport, Shreveport, LA 71103, USA
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10
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Straetmans JMJAA, Stuut M, Lacko M, Hoebers F, Speel EJM, Kremer B. Additional parameters to improve the prognostic value of the 8th edition of the UICC classification for human papillomavirus-related oropharyngeal tumors. Head Neck 2022; 44:1799-1815. [PMID: 35579041 PMCID: PMC9544856 DOI: 10.1002/hed.27084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 02/17/2022] [Accepted: 04/27/2022] [Indexed: 12/04/2022] Open
Abstract
Background The prognostic reliability of the UICC's TNM classification (8th edition) for human papillomavirus (HPV)‐positive tonsillar squamous cell carcinomas (TSCCs) compared to the 7th edition was explored, and its improvement by using additional anatomical and nonanatomical parameters. Methods One hundred and ten HPV‐positive and 225 HPV‐negative TSCCs were retrospectively analyzed. Survival was correlated with patient and tumor characteristics (7th and 8th edition UICC TNM classification). Results In HPV‐positive TSCCs, the 8th edition UICC's TNM classification correlated better with prognosis than the 7th edition. Also, smoking status was a stronger prognosticator of survival than UICC staging. Non‐ or former smokers had a 5‐year overall survival of 95.1% regardless of tumor stage. Furthermore, age (>65 years), cN3, and M1 classification were significant prognostic factors. Conclusion The prognostic value of the 8th edition UICC's TNM classification improved significantly when compared to the 7th edition. Nonetheless, further improvement is possible by adding nonanatomical factors (smoking, age >65 year) and separating N0‐N2 from N3.
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Affiliation(s)
- Jos M J A A Straetmans
- Department of Otorhinolaryngology and Head and Neck Surgery, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.,Department of Otorhinolaryngology and Head and Neck Surgery, Zuyderland Medical Center, Heerlen, the Netherlands
| | - Marijn Stuut
- Department of Otorhinolaryngology and Head and Neck Surgery, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Martin Lacko
- Department of Otorhinolaryngology and Head and Neck Surgery, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Frank Hoebers
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Ernst-Jan M Speel
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Bernd Kremer
- Department of Otorhinolaryngology and Head and Neck Surgery, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
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11
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Ferraguti G, Terracina S, Petrella C, Greco A, Minni A, Lucarelli M, Agostinelli E, Ralli M, de Vincentiis M, Raponi G, Polimeni A, Ceccanti M, Caronti B, Di Certo MG, Barbato C, Mattia A, Tarani L, Fiore M. Alcohol and Head and Neck Cancer: Updates on the Role of Oxidative Stress, Genetic, Epigenetics, Oral Microbiota, Antioxidants, and Alkylating Agents. Antioxidants (Basel) 2022; 11:145. [PMID: 35052649 PMCID: PMC8773066 DOI: 10.3390/antiox11010145] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/27/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancer (HNC) concerns more than 890,000 patients worldwide annually and is associated with the advanced stage at presentation and heavy outcomes. Alcohol drinking, together with tobacco smoking, and human papillomavirus infection are the main recognized risk factors. The tumorigenesis of HNC represents an intricate sequential process that implicates a gradual acquisition of genetic and epigenetics alterations targeting crucial pathways regulating cell growth, motility, and stromal interactions. Tumor microenvironment and growth factors also play a major role in HNC. Alcohol toxicity is caused both directly by ethanol and indirectly by its metabolic products, with the involvement of the oral microbiota and oxidative stress; alcohol might enhance the exposure of epithelial cells to carcinogens, causing epigenetic modifications, DNA damage, and inaccurate DNA repair with the formation of DNA adducts. Long-term markers of alcohol consumption, especially those detected in the hair, may provide crucial information on the real alcohol drinking of HNC patients. Strategies for prevention could include food supplements as polyphenols, and alkylating drugs as therapy that play a key role in HNC management. Indeed, polyphenols throughout their antioxidant and anti-inflammatory actions may counteract or limit the toxic effect of alcohol whereas alkylating agents inhibiting cancer cells' growth could reduce the carcinogenic damage induced by alcohol. Despite the established association between alcohol and HNC, a concerning pattern of alcohol consumption in survivors of HNC has been shown. It is of primary importance to increase the awareness of cancer risks associated with alcohol consumption, both in oncologic patients and the general population, to provide advice for reducing HNC prevalence and complications.
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Affiliation(s)
- Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (S.T.); (M.L.)
| | - Sergio Terracina
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (S.T.); (M.L.)
| | - Carla Petrella
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
| | - Antonio Greco
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Antonio Minni
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Marco Lucarelli
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (S.T.); (M.L.)
| | - Enzo Agostinelli
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Massimo Ralli
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Marco de Vincentiis
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Giammarco Raponi
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy;
| | - Antonella Polimeni
- Department of Odontostomatological and Maxillofacial Sciences, Sapienza University of Rome, 00185 Rome, Italy;
| | - Mauro Ceccanti
- SITAC, Società Italiana per il Trattamento dell’Alcolismo, 00184 Rome, Italy;
- SIFASD, Società Italiana Sindrome Feto-Alcolica, 00184 Rome, Italy
| | - Brunella Caronti
- Department of Human Neurosciences, Sapienza University of Rome, 00185 Rome, Italy;
| | - Maria Grazia Di Certo
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
| | - Christian Barbato
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
| | - Alessandro Mattia
- Ministero dell’Interno, Dipartimento della Pubblica Sicurezza, Direzione Centrale di Sanità, Centro di Ricerche e Laboratorio di Tossicologia Forense, 00185 Rome, Italy;
| | - Luigi Tarani
- Department of Pediatrics, Sapienza University Hospital of Rome, 00185 Rome, Italy;
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
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12
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Munari FF, Sichero L, Carloni AC, Lacerda CF, Nunes EM, de Oliveira ATT, Scapulatempo-Neto C, da Silva SRM, Crema E, Adad SJ, Rodrigues MAM, Henry MACA, Guimarães DP, Reis RM, Villa LL, Longatto-Filho A. Frequency of Human Papillomavirus Detection in Chagasic Megaesophagus Associated or Not with Esophageal Squamous Cell Carcinoma. Pathobiology 2021; 89:29-37. [PMID: 34818254 DOI: 10.1159/000518697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 07/26/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Chagasic megaesophagus (CM) as well as the presence of human papillomavirus (HPV) has been reported as etiological factors for esophageal squamous cell carcinoma (ESCC). OBJECTIVE We assessed the prevalence of HPV DNA in a series of ESCCs associated or not with CM. Data obtained were further correlated to the pathological and clinical data of affected individuals. METHODS A retrospective study was performed on 92 formalin-fixed and paraffin-embedded tissues collected from patients referred to 3 different hospitals in São Paulo, Brazil: Barretos Cancer Hospital, Barretos, São Paulo; Federal University of Triângulo Mineiro, Uberaba, Minas Gerais; and São Paulo State University, Botucatu, São Paulo. Cases were divided into 3 groups: (i) 24 patients with CM associated with ESCC (CM/ESCC); (ii) 37 patients with ESCC without CM (ESCC); and (iii) 31 patients with CM without ESCC (CM). Detection of HPV DNA was assessed in all samples by a genotyping assay combining multiplex polymerase chain reaction and bead-based Luminex technology. RESULTS We identified a high prevalence of high-risk HPV in patients in the CM group (12/31, 38.8%) and CM/ESCC (8/24, 33.3%), compared to individuals in the ESCC group (6/37, 16.3%). The individuals in the groups with cancer (ESCC and CM/ESCC) had a higher frequency of HPV-16 (4/9, 44.5% and 2/8, 25.0%). The other types of high-risk HPVs detected were HPV-31, 45, 51, 53, 56, 66, and 73. We also observed in some samples HPV coinfection by more than one viral type. Despite the high incidence of HPV, it did not show any association with the patient's clinical-pathological and molecular (TP53 mutation status) characteristics. CONCLUSION This is the first report of the presence of HPV DNA in CM associated with ESCC. HPV infection was more presence in megaesophagus lesions. Further studies are needed to confirm and better understand the role of persistent HPV infection in patients with CM.
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Affiliation(s)
| | - Laura Sichero
- Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo-ICESP, Cerqueira César, Brazil
| | | | - Croider Franco Lacerda
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Department of Digestive Surgery, Barretos Cancer Hospital, Barretos, Brazil
| | - Emily Montosa Nunes
- Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo-ICESP, Cerqueira César, Brazil
| | | | - Cristovam Scapulatempo-Neto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Department of Pathology, Diagnosis of Biopsies and Surgical Specimens, Barretos Cancer Hospital, Barretos, Brazil
| | | | - Eduardo Crema
- Department of Digestive Surgery and Pathology, Medical School, UFTM, Federal University of Triangulo Mineiro, Uberaba, Brazil
| | - Sheila Jorge Adad
- Departament of Gastroenterology Surgery and Pathology, Medical School, UNESP, São Paulo State University, Botucatu, Brazil
| | | | | | - Denise Peixoto Guimarães
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Department of Endoscopy, Barretos Cancer Hospital, Barretos, Brazil
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Luisa Lina Villa
- Center for Translational Research in Oncology, Instituto do Cancer do Estado de Sao Paulo-ICESP, Cerqueira César, Brazil.,Department of Radiology and Oncology, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo, Brazil
| | - Adhemar Longatto-Filho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.,Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,Department of Radiology and Oncology, Medical School, University of São Paulo, Butanta, Brazil.,Medical Laboratory of Medical Investigation (LIM) 14, Department of Pathology, Medical School, University of São Paulo, Butanta, Brazil
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13
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Causes and Consequences of HPV Integration in Head and Neck Squamous Cell Carcinomas: State of the Art. Cancers (Basel) 2021; 13:cancers13164089. [PMID: 34439243 PMCID: PMC8394665 DOI: 10.3390/cancers13164089] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/10/2021] [Accepted: 08/11/2021] [Indexed: 12/29/2022] Open
Abstract
A constantly increasing incidence in high-risk Human Papillomaviruses (HPV)s driven head and neck squamous cell carcinomas (HNSCC)s, especially of oropharyngeal origin, is being observed. During persistent infections, viral DNA integration into the host genome may occur. Studies are examining if the physical status of the virus (episomal vs. integration) affects carcinogenesis and eventually has further-reaching consequences on disease progression and outcome. Here, we review the literature of the most recent five years focusing on the impact of HPV integration in HNSCCs, covering aspects of detection techniques used (from PCR up to NGS approaches), integration loci identified, and associations with genomic and clinical data. The consequences of HPV integration in the human genome, including the methylation status and deregulation of genes involved in cell signaling pathways, immune evasion, and response to therapy, are also summarized.
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14
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Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma. Eur Arch Otorhinolaryngol 2021; 279:1435-1443. [PMID: 34046748 DOI: 10.1007/s00405-021-06894-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/18/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium. METHODS This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed. RESULTS There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis. CONCLUSION The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.
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15
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Näsman A, Holzhauser S, Kostopoulou ON, Zupancic M, Ährlund-Richter A, Du J, Dalianis T. Prognostic Markers and Driver Genes and Options for Targeted Therapy in Human-Papillomavirus-Positive Tonsillar and Base-of-Tongue Squamous Cell Carcinoma. Viruses 2021; 13:v13050910. [PMID: 34069114 PMCID: PMC8156012 DOI: 10.3390/v13050910] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 05/10/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
The incidence of Human-papillomavirus-positive (HPV+) tonsillar and base-of-tongue squamous cell carcinoma (TSCC and BOTSCC, respectively) is increasing epidemically, but they have better prognosis than equivalent HPV-negative (HPV−) cancers, with roughly 80% vs. 50% 3-year disease-free survival, respectively. The majority of HPV+ TSCC and BOTSCC patients therefore most likely do not require the intensified chemoradiotherapy given today to head and neck cancer patients and would with de-escalated therapy avoid several severe side effects. Moreover, for those with poor prognosis, survival has not improved, so better-tailored alternatives are urgently needed. In line with refined personalized medicine, recent studies have focused on identifying predictive markers and driver cancer genes useful for better stratifying patient treatment as well as for targeted therapy. This review presents some of these endeavors and briefly describes some recent experimental progress and some clinical trials with targeted therapy.
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Affiliation(s)
- Anders Näsman
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum J6:20, Karolinska University Hospital, 171 64 Stockholm, Sweden; (A.N.); (S.H.); (O.N.K.); (M.Z.); (A.Ä.-R.)
| | - Stefan Holzhauser
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum J6:20, Karolinska University Hospital, 171 64 Stockholm, Sweden; (A.N.); (S.H.); (O.N.K.); (M.Z.); (A.Ä.-R.)
| | - Ourania N. Kostopoulou
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum J6:20, Karolinska University Hospital, 171 64 Stockholm, Sweden; (A.N.); (S.H.); (O.N.K.); (M.Z.); (A.Ä.-R.)
| | - Mark Zupancic
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum J6:20, Karolinska University Hospital, 171 64 Stockholm, Sweden; (A.N.); (S.H.); (O.N.K.); (M.Z.); (A.Ä.-R.)
| | - Andreas Ährlund-Richter
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum J6:20, Karolinska University Hospital, 171 64 Stockholm, Sweden; (A.N.); (S.H.); (O.N.K.); (M.Z.); (A.Ä.-R.)
| | - Juan Du
- Department of Microbiology, Tumor Biology and Cellular Biology, Karolinska Institutet, Biomedicum, 171 77 Stockholm, Sweden;
| | - Tina Dalianis
- Department of Oncology-Pathology, Karolinska Institutet, Bioclinicum J6:20, Karolinska University Hospital, 171 64 Stockholm, Sweden; (A.N.); (S.H.); (O.N.K.); (M.Z.); (A.Ä.-R.)
- Correspondence:
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16
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Mulder FJ, Klufah F, Janssen FME, Farshadpour F, Willems SM, de Bree R, zur Hausen A, van den Hout MFCM, Kremer B, Speel EJM. Presence of Human Papillomavirus and Epstein-Barr Virus, but Absence of Merkel Cell Polyomavirus, in Head and Neck Cancer of Non-Smokers and Non-Drinkers. Front Oncol 2021; 10:560434. [PMID: 33552950 PMCID: PMC7855709 DOI: 10.3389/fonc.2020.560434] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 11/30/2020] [Indexed: 12/14/2022] Open
Abstract
OBJECTIVE Determine the presence and prognostic value of human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCPyV), and cell cycle proteins in head and neck squamous cell carcinoma (HNSCC) of non-smokers and non-drinkers (NSND). METHODS Clinical characteristics and tumors of 119 NSND with HNSCC were retrospectively collected and analyzed on tissue microarrays. RNAscope in situ hybridization (ISH) was used to screen for the presence of HPV and MCPyV mRNA. Immunohistochemistry was performed for expression of p16 as surrogate marker for HPV, Large T-antigen for MCPyV, and cell cycle proteins p53 and pRb. Positive virus results were confirmed with polymerase chain reaction. For EBV, EBV encoded RNA ISH was performed. Differences in 5-year survival between virus positive and negative tumors were determined by log rank analysis. RESULTS All oropharyngeal tumors (OPSCC) (n = 10) were HPV-positive, in addition to one oral (OSCC) and one nasopharyngeal tumor (NPSCC). The other three NPSCC were EBV-positive. MCPyV was not detected. Patients with HPV or EBV positive tumors did not have a significantly better 5-year disease free or overall survival. Over 70% of virus negative OSCC showed mutant-type p53 expression. CONCLUSION In this cohort, all OPSCC and NPSCC showed HPV or EBV presence. Besides one OSCC, all other oral (n = 94), hypopharyngeal (n = 1), and laryngeal (n = 9) tumors were HPV, EBV, and MCPyV negative. This argues against a central role of these viruses in the ethiopathogenesis of tumors outside the oro- and nasopharynx in NSND. So, for the majority of NSND with virus negative OSCC, more research is needed to understand the carcinogenic mechanisms in order to consider targeted therapeutic options.
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Affiliation(s)
- Frans J. Mulder
- Department of Otorhinolaryngology and Head & Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Faisal Klufah
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
- Department of Laboratory Medicine, Faculty of Applied Medical Sciences, Albaha University, Albaha, Saudi Arabia
| | - Famke M. E. Janssen
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | | | - Stefan M. Willems
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
- Department of Pathology, University Medical Center Groningen, Groningen, Netherlands
| | - Remco de Bree
- Department of Head and Neck Surgical Oncology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Axel zur Hausen
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Mari F. C. M. van den Hout
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Bernd Kremer
- Department of Otorhinolaryngology and Head & Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Ernst-Jan M. Speel
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
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17
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Aggarwal N, Yadav J, Thakur K, Bibban R, Chhokar A, Tripathi T, Bhat A, Singh T, Jadli M, Singh U, Kashyap MK, Bharti AC. Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns. Front Cell Infect Microbiol 2020. [PMID: 33344262 DOI: 10.3389/fcimb.2020.537650,] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers. Collectively, HNSCC ranks sixth in incidence rate worldwide. Apart from classical risk factors like tobacco and alcohol, infection of human papillomavirus (HPV) is emerging as a discrete risk factor for HNSCC. HPV-positive HNSCC represent a distinct group of diseases that differ in their clinical presentation. These lesions are well-differentiated, occur at an early age, and have better prognosis. Epidemiological studies have demonstrated a specific increase in the proportions of the HPV-positive HNSCC. HPV-positive and HPV-negative HNSCC lesions display different disease progression and clinical response. For tumorigenic-transformation, HPV essentially requires a permissive cellular environment and host cell factors for induction of viral transcription. As the spectrum of host factors is independent of HPV infection at the time of viral entry, presumably entry of HPV only selects host cells that are permissive to establishment of HPV infection. Growing evidence suggest that HPV plays a more active role in a subset of HNSCC, where they are transcriptionally-active. A variety of factors provide a favorable environment for HPV to become transcriptionally-active. The most notable are the set of transcription factors that have direct binding sites on the viral genome. As HPV does not have its own transcription machinery, it is fully dependent on host transcription factors to complete the life cycle. Here, we review and evaluate the current evidence on level of a subset of host transcription factors that influence viral genome, directly or indirectly, in HNSCC. Since many of these transcription factors can independently promote carcinogenesis, the composition of HPV permissive transcription factors in a tumor can serve as a surrogate marker of a separate molecularly-distinct class of HNSCC lesions including those cases, where HPV could not get a chance to infect but may manifest better prognosis.
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Affiliation(s)
- Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Rakhi Bibban
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Anjali Bhat
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Ujala Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Manoj K Kashyap
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Amity Medical School, Stem Cell Institute, Amity University Haryana, Amity Education Valley Panchgaon, Gurugram, India
| | - Alok C Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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Bojaxhiu B, Shrestha BK, Luterbacher P, Elicin O, Shelan M, Macpherson AJS, Heimgartner B, Giger R, Aebersold DM, Zaugg K. Unplanned hospitalizations in patients with locoregionally advanced head and neck cancer treated with (chemo)radiotherapy with and without prophylactic percutaneous endoscopic gastrostomy. Radiat Oncol 2020; 15:281. [PMID: 33317602 PMCID: PMC7737384 DOI: 10.1186/s13014-020-01727-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/06/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Current studies about percutaneous endoscopic gastrostomy (PEG) tube placement report equivalent patient outcomes with prophylactic PEG tubes (pPEGs) versus common nutritional support. Unreported was if omitting a pPEG is associated with an increased risk of complications leading to a treatment-related unplanned hospitalization (TRUH). METHODS TRUHs were retrospectively analyzed in patients with advanced head and neck squamous cell carcinoma (n = 310) undergoing (chemo)radiotherapy with (pPEG) or without PEG (nPEG). RESULTS In 88 patients (28%), TRUH was reported. One of the leading causes of TRUH in nPEG patients was inadequate oral intake (n = 16, 13%), and in pPEG patients, complications after PEG tube insertion (n = 12, 10%). Risk factors for TRUH were poor performance status, tobacco use, and surgical procedures. CONCLUSIONS Omitting pPEG tube placement without increasing the risk of an unplanned hospitalization due to dysphagia, dehydration or malnutrition, is an option in patients being carefully monitored. Patients aged > 60 years with hypopharyngeal carcinoma, tobacco consumption, and poor performance status appear at risk of PEG tube-related complications leading to an unplanned hospitalization.
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Affiliation(s)
- Beat Bojaxhiu
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department of Nuclear Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.,Department of Radiation Oncology, Stadtspital Triemli, Birmensdorferstrasse 497, 8063, Zurich, Switzerland
| | - Binaya K Shrestha
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Pascal Luterbacher
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Olgun Elicin
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Mohamed Shelan
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Andrew J S Macpherson
- Department of Visceral Surgery and Medicine, Division of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Benjamin Heimgartner
- Department of Visceral Surgery and Medicine, Division of Gastroenterology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Roland Giger
- Department of Otorhinolaryngology, Head and Neck Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Daniel M Aebersold
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Kathrin Zaugg
- Department of Radiation Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. .,Department of Radiation Oncology, Stadtspital Triemli, Birmensdorferstrasse 497, 8063, Zurich, Switzerland.
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Aggarwal N, Yadav J, Thakur K, Bibban R, Chhokar A, Tripathi T, Bhat A, Singh T, Jadli M, Singh U, Kashyap MK, Bharti AC. Human Papillomavirus Infection in Head and Neck Squamous Cell Carcinomas: Transcriptional Triggers and Changed Disease Patterns. Front Cell Infect Microbiol 2020; 10:537650. [PMID: 33344262 PMCID: PMC7738612 DOI: 10.3389/fcimb.2020.537650] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 11/02/2020] [Indexed: 02/05/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of cancers. Collectively, HNSCC ranks sixth in incidence rate worldwide. Apart from classical risk factors like tobacco and alcohol, infection of human papillomavirus (HPV) is emerging as a discrete risk factor for HNSCC. HPV-positive HNSCC represent a distinct group of diseases that differ in their clinical presentation. These lesions are well-differentiated, occur at an early age, and have better prognosis. Epidemiological studies have demonstrated a specific increase in the proportions of the HPV-positive HNSCC. HPV-positive and HPV-negative HNSCC lesions display different disease progression and clinical response. For tumorigenic-transformation, HPV essentially requires a permissive cellular environment and host cell factors for induction of viral transcription. As the spectrum of host factors is independent of HPV infection at the time of viral entry, presumably entry of HPV only selects host cells that are permissive to establishment of HPV infection. Growing evidence suggest that HPV plays a more active role in a subset of HNSCC, where they are transcriptionally-active. A variety of factors provide a favorable environment for HPV to become transcriptionally-active. The most notable are the set of transcription factors that have direct binding sites on the viral genome. As HPV does not have its own transcription machinery, it is fully dependent on host transcription factors to complete the life cycle. Here, we review and evaluate the current evidence on level of a subset of host transcription factors that influence viral genome, directly or indirectly, in HNSCC. Since many of these transcription factors can independently promote carcinogenesis, the composition of HPV permissive transcription factors in a tumor can serve as a surrogate marker of a separate molecularly-distinct class of HNSCC lesions including those cases, where HPV could not get a chance to infect but may manifest better prognosis.
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Affiliation(s)
- Nikita Aggarwal
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Joni Yadav
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Kulbhushan Thakur
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Rakhi Bibban
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Arun Chhokar
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tanya Tripathi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Anjali Bhat
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Ujala Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
| | - Manoj K. Kashyap
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
- Amity Medical School, Stem Cell Institute, Amity University Haryana, Amity Education Valley Panchgaon, Gurugram, India
| | - Alok C. Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India
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20
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Mulder FJ, Pierssens DDCG, Baijens LWJ, Kremer B, Speel EJM. Evidence for different molecular parameters in head and neck squamous cell carcinoma of nonsmokers and nondrinkers: Systematic review and meta-analysis on HPV, p16, and TP53. Head Neck 2020; 43:303-322. [PMID: 33098216 PMCID: PMC7756438 DOI: 10.1002/hed.26513] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/30/2020] [Accepted: 10/13/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The goal of this review was to present an overview of the currently identified molecular parameters in head and neck squamous cell carcinoma (HNSCC) of nonsmokers and nondrinkers (NSND). METHODS Following the PRISMA guidelines, a systematic search was performed using the electronic databases PubMed, Embase, and Google Scholar. RESULTS Of the 902 analyzed unique studies, 74 were included in a quantitative synthesis and 24 in a meta-analysis. Human papillomavirus (HPV) was reported as a molecular parameter in 38 studies, followed by p16 and TP53 (23 and 14 studies, respectively). The variety of other molecular parameters concerned sporadic findings in small numbers of NSND. CONCLUSIONS HNSCC in NSND is more often related to HPV and p16 overexpression compared to tumors of smokers-drinkers. In a third of virus-negative tumors, TP53 mutations were detected with a mutational profile associated with aging and ultraviolet light exposure rather than to tobacco consumption.
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Affiliation(s)
- Frans J Mulder
- Department of Otorhinolaryngology and Head & Neck Surgery, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Damiana D C G Pierssens
- Department of Oral and Cranio-Maxillofacial Surgery, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Laura W J Baijens
- Department of Otorhinolaryngology and Head & Neck Surgery, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Bernd Kremer
- Department of Otorhinolaryngology and Head & Neck Surgery, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Ernst-Jan M Speel
- Department of Pathology, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, Netherlands
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21
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Guan Y, Wang G, Fails D, Nagarajan P, Ge Y. Unraveling cancer lineage drivers in squamous cell carcinomas. Pharmacol Ther 2020; 206:107448. [PMID: 31836455 PMCID: PMC6995404 DOI: 10.1016/j.pharmthera.2019.107448] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
Cancer hijacks embryonic development and adult wound repair mechanisms to fuel malignancy. Cancer frequently originates from de-regulated adult stem cells or progenitors, which are otherwise essential units for postnatal tissue remodeling and repair. Cancer genomics studies have revealed convergence of multiple cancers across organ sites, including squamous cell carcinomas (SCCs), a common group of cancers arising from the head and neck, esophagus, lung, cervix and skin. In this review, we summarize our current knowledge on the molecular drivers of SCCs, including these five major organ sites. We especially focus our discussion on lineage dependent driver genes and pathways, in the context of squamous development and stratification. We then use skin as a model to discuss the notion of field cancerization during SCC carcinogenesis, and cancer as a wound that never heals. Finally, we turn to the idea of context dependency widely observed in cancer driver genes, and outline literature support and possible explanations for their lineage specific functions. Through these discussions, we aim to provide an up-to-date summary of molecular mechanisms driving tumor plasticity in squamous cancers. Such basic knowledge will be helpful to inform the clinics for better stratifying cancer patients, revealing novel drug targets and providing effective treatment options.
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Affiliation(s)
- Yinglu Guan
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Guan Wang
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Danielle Fails
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
| | - Yejing Ge
- Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
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22
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Venkatesan AM, Menias CO, Jones KM, Rauch GM, Stafford RJ, Klopp AH. MRI for Radiation Therapy Planning in Human Papillomavirus-associated Gynecologic Cancers. Radiographics 2019; 39:1476-1500. [PMID: 31498740 DOI: 10.1148/rg.2019180121] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Locally advanced human papillomavirus (HPV)-associated gynecologic cancers, including cervical, vaginal, and vulvar cancers, are treated primarily with radiation therapy (RT). Cervical cancer remains a leading cause of cancer death among women worldwide. The superior soft-tissue resolution of MRI compared with other imaging modalities makes it an ideal modality for RT planning, execution, and follow-up of these malignancies. This superiority has been corroborated in the literature when comparing MRI-based RT planning to radiography-based conventional treatment planning approaches. In 2005, the Groupe Européen de Curiethérapie and the European Society for Radiation Therapy and Oncology guidelines underscored the central role of MRI for successful implementation of three-dimensional image-based cervical cancer brachytherapy. The delineation of both gross tumor volume and clinical tumor volume for brachytherapy is performed at the time of each brachytherapy application, on the basis of the findings depicted on anatomic MR images. Contemporary knowledge concerning the role of MRI for RT planning in HPV-associated gynecologic cancers warrants an understanding of the epidemiology and clinical manifestations of these cancers, as well as knowledge of MRI protocol for cancer staging, selection of RT candidates, brachytherapy implant assessment, posttreatment surveillance, and delineation of treatment-related complications. Technical requirements, patient preparation, and image acquisition protocols are detailed in this review, and imaging-based treatment protocols are summarized. Knowledge of these fundamental concepts enables the radiologist to play an important role in diagnosis, staging, and posttreatment follow-up, helping to guide radiation oncologists and other clinicians in the management of these malignancies.©RSNA, 2019.
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Affiliation(s)
- Aradhana M Venkatesan
- From the Section of Abdominal Imaging, Department of Diagnostic Radiology (A.M.V., K.M.J., G.M.R.) and Department of Radiation Oncology (A.H.K.), University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT 15.6074, MSC 1182, Houston, TX 77030; and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., R.J.S.)
| | - Christine O Menias
- From the Section of Abdominal Imaging, Department of Diagnostic Radiology (A.M.V., K.M.J., G.M.R.) and Department of Radiation Oncology (A.H.K.), University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT 15.6074, MSC 1182, Houston, TX 77030; and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., R.J.S.)
| | - Kyle M Jones
- From the Section of Abdominal Imaging, Department of Diagnostic Radiology (A.M.V., K.M.J., G.M.R.) and Department of Radiation Oncology (A.H.K.), University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT 15.6074, MSC 1182, Houston, TX 77030; and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., R.J.S.)
| | - Gaiane M Rauch
- From the Section of Abdominal Imaging, Department of Diagnostic Radiology (A.M.V., K.M.J., G.M.R.) and Department of Radiation Oncology (A.H.K.), University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT 15.6074, MSC 1182, Houston, TX 77030; and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., R.J.S.)
| | - R Jason Stafford
- From the Section of Abdominal Imaging, Department of Diagnostic Radiology (A.M.V., K.M.J., G.M.R.) and Department of Radiation Oncology (A.H.K.), University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT 15.6074, MSC 1182, Houston, TX 77030; and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., R.J.S.)
| | - Ann H Klopp
- From the Section of Abdominal Imaging, Department of Diagnostic Radiology (A.M.V., K.M.J., G.M.R.) and Department of Radiation Oncology (A.H.K.), University of Texas MD Anderson Cancer Center, 1400 Pressler St, FCT 15.6074, MSC 1182, Houston, TX 77030; and Department of Radiology, Mayo Clinic, Scottsdale, Ariz (C.O.M., R.J.S.)
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23
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"Expression of p16 in oral leukoplakia and oral squamous cell carcinoma and correlation of its expression with individual atypical features". J Oral Biol Craniofac Res 2019; 9:156-160. [PMID: 30963022 DOI: 10.1016/j.jobcr.2019.03.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 03/04/2019] [Accepted: 03/06/2019] [Indexed: 11/20/2022] Open
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24
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Götz C, Bischof C, Wolff KD, Kolk A. Detection of HPV infection in head and neck cancers: Promise and pitfalls in the last ten years: A meta-analysis. Mol Clin Oncol 2019; 10:17-28. [PMID: 30655973 PMCID: PMC6313947 DOI: 10.3892/mco.2018.1749] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 08/09/2018] [Indexed: 12/16/2022] Open
Abstract
The current controversial discussion on the disease-specific survival of patients with human papillomavirus (HPV)-positive (+) and -negative (-) squamous cell carcinoma (SCC) of the head neck region was the motivation for the present meta-analysis. Different detection methods for HPV are available, though these often lack sensitivity. As a consequence, there may be false interpretation of HPV positivity. A bias concerning HPV status and therefore also survival rates is serving a non-durable relevance in the discussion of tailored therapies. A literature search was performed via the online database PubMed/NCBI, and data extraction and statistical analysis were conducted. A total of 139 studies published between 2004 and 2014 were evaluated in the present meta-analysis. The HPV detection methods, patient characteristics, tumor localizations and stages, as well as (neo-) adjuvant therapies and survival times were analyzed. The average incidence rates of HPV+ patients with oropharyngeal tumors were higher than those of patients with cancers of other regions of the head and neck. Upon evaluating the results of different detection methods no significant differences were identified. We have compared the HPV incidence rates of each detection method, when studies have used more than one. Regarding overall survival, the pooled adjusted hazard ratio (HR) for oropharyngeal SCC was 0.31 [95% confidence interval (CI)=0.27-0.36]. Unfortunately, only 3 equivalent studies were available on nonoropharyngeal tumors, for which the pooled adjusted HR was 1 (95% CI=0.73-1.36). Overall, the evaluation demonstrated that the survival rates reported in numerous studies were not evaluated multifactorially and important confounders were excluded from the statistics. The HPV detection methods used were often not sufficient in representing HPV positivity. In addition, oropharyngeal and oral SCCs were assessed together in the localization. The widely differing number of HPV+ patients in each of the various studies may be explained by insufficient detection methods and by a lack of localization distinction. The considerations of a tailored therapy according to HPV status should be rejected based on the present information. The previously published studies should be read critically and do not represent a basis for therapeutic decisions.
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Affiliation(s)
- Carolin Götz
- Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, D-81675 Munich, Germany
| | - Clara Bischof
- Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, D-81675 Munich, Germany
| | - Klaus-Dietrich Wolff
- Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, D-81675 Munich, Germany
| | - Andreas Kolk
- Department of Oral and Maxillofacial Surgery, Technical University of Munich, Klinikum Rechts der Isar, D-81675 Munich, Germany
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25
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Abstract
Since their discovery as the etiologic agents of cervical cancer in the mid-1970s, human papillomaviruses (HPVs) have been linked with a growing number of epithelial-derived tumors, including head and neck squamous cell carcinomas. HPV demonstrates a particular predilection for causing tumors of the oropharynx, with the majority of cases involving infection with high-oncogenic risk HPV-16. People living with HIV are at increased risk of infection with HPV- and HPV-related oral complications even with adequate control of their HIV infection with antiretroviral therapy. In this chapter, we discuss the molecular mechanisms that underlie HPV-mediated oncogenesis in the oropharynx. We also describe the progress that has been made in understanding the epidemiology of oral HPV infection and the determinants of oral HPV-related pathology. Finally, we examine what can be done to treat and prevent oral HPV infection, benign lesions, and cancer, particularly in the context of the HIV-positive patient.
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26
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Kiessling SY, Broglie MA, Soltermann A, Huber GF, Stoeckli SJ. Comparison of PI3K Pathway in HPV-Associated Oropharyngeal Cancer With and Without Tobacco Exposure. Laryngoscope Investig Otolaryngol 2018; 3:283-289. [PMID: 30186959 PMCID: PMC6119789 DOI: 10.1002/lio2.175] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/23/2018] [Accepted: 04/30/2018] [Indexed: 12/21/2022] Open
Abstract
Objectives The aim of the study was to evaluate whether HPV associated OPSCC with tobacco exposure follows a different carcinogenic pathway compared to HPV associated OPSCC without tobacco exposure and to investigate its prognostic significance. The question was addressed with focus on components of the PI3K pathway. Methods 184 patients with newly diagnosed OPSCC treated with curative intent were consecutively enrolled. The expression level of p16, p53, PI3K, mTOR, and PTEN was assessed by immunohistochemistry and analyzed in relation to the risk factors HPV status and tobacco exposure. Results 94 of 184 (51%) patients were p16 positive, p53 overexpression was detected in 48 of 184 (26%) cases. PI3K overexpression with 70 of 184 (38%) cases was significantly higher in p16 positive tumors. mTOR overexpression was present in 90 of 184 (49%) cases and significantly higher in p16 negative tumors. PTEN loss was found in 42 of 184 (23%) cases without association to p16 expression. p16 positive OPSCC showed lower rates of p53 expression and mTOR expression as well as higher rates of PI3K expression irrespective of tobacco exposure. Survival analysis showed a distinct intermediate survival rate of p16 positive smokers. The markers PI3K, mTOR, and PTEN did not have a significant impact on survival. Conclusion HPV associated OPSCC with tobacco exposure follows the same expression level of the PI3K pathway as HPV associated OPSCC without tobacco exposure. The impaired survival rate of the intermediate risk group cannot be explained by different expression patterns of PI3K, mTOR, and PTEN. Level of Evidence 2b
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Affiliation(s)
- Si-Young Kiessling
- Department of Otorhinolaryngology, Head and Neck Surgery Cantonal Hospital of St. Gallen St. Gallen Switzerland
| | - Martina Anja Broglie
- Department of Otorhinolaryngology, Head and Neck Surgery Cantonal Hospital of St. Gallen St. Gallen Switzerland
| | - Alex Soltermann
- Institute of Pathology and Molecular Pathology University Hospital of Zurich Zurich Switzerland
| | - Gerhard Frank Huber
- Department of Otorhinolaryngology, Head and Neck Surgery University Hospital of Zurich Zurich Switzerland.,University of Zurich Zurich Switzerland
| | - Sandro Johannes Stoeckli
- Department of Otorhinolaryngology, Head and Neck Surgery Cantonal Hospital of St. Gallen St. Gallen Switzerland
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27
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Khanal S, Shumway BS, Zahin M, Redman RA, Strickley JD, Trainor PJ, Rai SN, Ghim SJ, Jenson AB, Joh J. Viral DNA integration and methylation of human papillomavirus type 16 in high-grade oral epithelial dysplasia and head and neck squamous cell carcinoma. Oncotarget 2018; 9:30419-30433. [PMID: 30100997 PMCID: PMC6084396 DOI: 10.18632/oncotarget.25754] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 05/25/2018] [Indexed: 12/19/2022] Open
Abstract
This study evaluated the integration and methlyation of human papillomavirus type 16 (HPV16) in head and neck squamous cell carcinoma (HNSCC) and its oral precursor, high-grade oral epithelial dysplasia (hgOED). Archival samples of HPV16-positive hgOED (N = 19) and HNSCC (N = 15) were evaluated, along with three HNSCC (UMSCC-1, -47 and -104) and two cervical cancer (SiHa and CaSki) cell lines. HgOED cases were stratified into three groups with increasing degrees of cytologic changes (mitosis, karyorrhexis and apoptosis). The viral load was higher and the E2/E6 ratio lower (indicating a greater tendency toward viral integration) in group 3 than in groups 1 or 2 (p = 0.002, 0.03). Methylation was not observed in hgOED cases and occurred variably in only three HNSCC cases (26.67%, 60.0% and 93.3%). In HNSCC cell lines, lower E7 expression correlated with higher levels of methylation. HgOED with increased cytologic change, now termed HPV-associated oral epithelial dysplasia (HPV-OED), exhibited an increased viral load and a tendency toward DNA integration, suggesting a potentially increased risk for malignant transformation. More detailed characterization and clinical follow-up of HPV-OED patients is needed to determine whether HPV-OED is a true precursor to HPV-associated HNSCC and to clarify the involvement of HPV in HNSCC carcinogenesis.
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Affiliation(s)
- Sujita Khanal
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Brian S Shumway
- Department of Surgical and Hospital Dentistry, University of Louisville School of Dentistry, Louisville, KY, USA
| | - Maryam Zahin
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Rebecca A Redman
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.,Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA
| | - John D Strickley
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.,Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA
| | - Patrick J Trainor
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Shesh N Rai
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Shin-Je Ghim
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | | | - Joongho Joh
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.,Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA.,Center for Predictive Medicine, University of Louisville, Louisville, KY, USA
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Sannigrahi MK, Sharma R, Panda NK, Khullar M. Role of non-coding RNAs in head and neck squamous cell carcinoma: A narrative review. Oral Dis 2017; 24:1417-1427. [PMID: 28941018 DOI: 10.1111/odi.12782] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 08/23/2017] [Accepted: 09/08/2017] [Indexed: 12/13/2022]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with high recurrence, metastasis, and poor treatment outcome. Recent studies have reported that non-coding RNA (ncRNA) might play critical role in regulating different types of cancer. MicroRNAs (miRs) are short ncRNAs (20-25 nucleotides) responsible for post-transcriptional regulation of gene expression and may have a role in oncogenesis by acting as oncomiRs or tumor suppressor miRs. Long non-coding RNAs (lncRNAs) are heterogenous group of ncRNAs more than 200 nucleotides long, can act in cis and/or in trans, and have been also implicated in carcinogenesis. These molecules have been suggested to be promising candidates as diagnostic and prognostic biomarkers and for development of novel therapeutic approaches. In this review, we have summarized recent findings on role of these ncRNAs in HPV-negative (HPV-ve) and HPV-positive (HPV+ve) HNSCC. The available literature supports differential expression of both microRNAs and long non-coding RNAs, which include oncogenic ncRNAs (miR-21, miR-31, miR-155, miR-211, HOTAIR, and MALAT1) and tumor suppressor ncRNAs (let7d, miR-17, miR-375, miR-139, and MEG3) in HPV+ve HNSCC tumors as compared to HPV-ve tumors and they have distinct role in the pathophysiology of these two types of HNSCCs.
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Affiliation(s)
- M K Sannigrahi
- Department of Otolaryngology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - R Sharma
- Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India
| | - N K Panda
- Department of Otolaryngology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - M Khullar
- Department of Experimental Medicine and Biotechnology, PGIMER, Chandigarh, India
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Zargar-Shoshtari K, Sharma P, Spiess PE. Insight into novel biomarkers in penile cancer: Redefining the present and future treatment paradigm? Urol Oncol 2017; 36:433-439. [PMID: 29103967 DOI: 10.1016/j.urolonc.2017.10.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 07/20/2017] [Accepted: 10/10/2017] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Biomarkers are increasingly used in the diagnosis and management of various malignancies. Selected biomarkers may also play a role in management of certain cases of penile carcinoma. In this article, we provide an overview of the clinical role of such markers in the management of penile cancer. METHOD This is a nonsystematic review of relevant literature assessing biomarkers in penile carcinoma. RESULTS Evidence of infections with human papillomavirus and its surrogate markers may have important prognostic value in patients with localized or metastatic penile cancer. Squamous cell carcinoma antigen, p53, C-reactive protein, Ki-67, proliferating cell nuclear antigen, cyclin D1, as well as other markers have been studied with various degree of evidence in support of clinical utility in penile cancer. CONCLUSIONS No single marker may have all the answers, and future research should focus on genomic analysis of individual penile tumors, attempting to identify specific targets for treatment.
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Affiliation(s)
| | - Pranav Sharma
- Department of Urology, Texas Tech Health Sciences Center, Lubbock, TX
| | - Philippe E Spiess
- Departments of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL.
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Dunn LA, Fury MG, Sherman EJ, Ho AA, Katabi N, Haque SS, Pfister DG. Phase I study of induction chemotherapy with afatinib, ribavirin, and weekly carboplatin and paclitaxel for stage IVA/IVB human papillomavirus-associated oropharyngeal squamous cell cancer. Head Neck 2017; 40:233-241. [PMID: 28963790 DOI: 10.1002/hed.24938] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 07/12/2017] [Accepted: 07/27/2017] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The human papillomavirus (HPV) E6 oncoprotein enhances the oncogenic potential of ErbB proteins in HPV-related malignancies. This phase I study evaluates the addition of afatinib, an ErbB family inhibitor, and ribavirin to paclitaxel and carboplatin induction chemotherapy in HPV-associated, locally advanced oropharyngeal squamous cell carcinoma (SCC). METHODS This dose escalation study included 2 doses of oral afatinib: 30 and 40 mg daily. Ribavirin dosing was weight based. Paclitaxel (80 mg/m2 ) and carboplatin (area under the curve [AUC] 1.5) were administered on days 1 and 8 of each 21-day cycle. After 3 cycles, patients were removed from protocol to receive definitive treatment. RESULTS Among 10 patients, there were no dose-limiting toxicities. Six patients (67%) had unconfirmed objective partial responses. The 2-year progression-free survival rate was 75%. CONCLUSION Afatinib, ribavirin, paclitaxel, and carboplatin induction chemotherapy is safe and well tolerated. The phase II recommended dose of afatinib is 40 mg oral daily in this combination regimen.
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Affiliation(s)
- Lara A Dunn
- Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Matthew G Fury
- Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eric J Sherman
- Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alan A Ho
- Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nora Katabi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sofia S Haque
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David G Pfister
- Department of Medicine, Head and Neck Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
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Ma HL, Jin SF, Ju WT, Fu Y, Tu YY, Wang LZ, Jiang-Li, Zhang ZY, Zhong LP. Stathmin is overexpressed and regulated by mutant p53 in oral squamous cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2017; 36:109. [PMID: 28806997 PMCID: PMC5556353 DOI: 10.1186/s13046-017-0575-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Accepted: 07/31/2017] [Indexed: 12/23/2022]
Abstract
Background The aim of this study was to investigate the oncogenic function and regulatory mechanism of stathmin in oral squamous cell carcinoma (OSCC). Methods Two-dimensional electrophoresis and liquid chromatography-tandem mass chromatography were applied to screen differentiated proteins during carcinogenesis in OSCC. Cell Counting Kit-8 (CCK-8) assays, colony formation, migration, flow cytometry, immunofluorescence and a xenograft model were used to detect the function of stathmin. The correlation between stathmin and p53 expression was analyzed using immunohistochemistry. Mutant/wild type p53 plasmids and small interfering RNA were used to examine the regulation of stathmin. Chromatin immunoprecipitation assays and luciferase assays were performed to detect the transcriptional activation of stathmin by p53. Results Overexpression of stathmin was screened and confirmed in OSCC patients and cell lines. Silencing expression of stathmin inhibited proliferation, colony formation and migration and promoted apoptosis. Poly ADP ribose polymerase (PARP) and cyclin-dependent kinase 1 (cdc2) were activated after silencing the expression of stathmin. Suppression of tumorigenicity was also confirmed in vivo. Mutant p53 transcriptionally activated the expression of stathmin in HN6 and HN13 cancer cells, but not in HN30 cells harboring wild type p53. Conclusions These results suggest that stathmin acts as an oncogene and is transcriptionally regulated by mutant p53, but not by wild-type p53. Stathmin could be a potential anti-tumor therapeutic target in OSCC. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0575-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Hai-Long Ma
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Shu-Fang Jin
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Wu-Tong Ju
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Yong Fu
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Yao-Yao Tu
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China
| | - Li-Zhen Wang
- Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiang-Li
- Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhi-Yuan Zhang
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China.
| | - Lai-Ping Zhong
- Department of Oral & Maxillofacial-Head & Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, No 639, Zhizaoju Rd, Shanghai, 200011, China.
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Morgan IM, DiNardo LJ, Windle B. Integration of Human Papillomavirus Genomes in Head and Neck Cancer: Is It Time to Consider a Paradigm Shift? Viruses 2017; 9:v9080208. [PMID: 28771189 PMCID: PMC5580465 DOI: 10.3390/v9080208] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2017] [Revised: 07/28/2017] [Accepted: 07/31/2017] [Indexed: 12/14/2022] Open
Abstract
Human papillomaviruses (HPV) are detected in 70–80% of oropharyngeal cancers in the developed world, the incidence of which has reached epidemic proportions. The current paradigm regarding the status of the viral genome in these cancers is that there are three situations: one where the viral genome remains episomal, one where the viral genome integrates into the host genome and a third where there is a mixture of both integrated and episomal HPV genomes. Our recent work suggests that this third category has been mischaracterized as having integrated HPV genomes; evidence indicates that this category consists of virus–human hybrid episomes. Most of these hybrid episomes are consistent with being maintained by replication from HPV origin. We discuss our evidence to support this new paradigm, how such genomes can arise, and more importantly the implications for the clinical management of HPV positive head and neck cancers following accurate determination of the viral genome status.
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Affiliation(s)
- Iain M Morgan
- Philips Institute for Oral Health Research, Virginia Commonwealth University (VCU) School of Dentistry, Department of Oral and Craniofacial Molecular Biology, Richmond, VA 23298, USA.
- VCU Massey Cancer Center, Richmond, VA 23298, USA.
| | - Laurence J DiNardo
- VCU Massey Cancer Center, Richmond, VA 23298, USA.
- VCU Department of Otolaryngology, Richmond, VA 23298, USA.
| | - Brad Windle
- Philips Institute for Oral Health Research, Virginia Commonwealth University (VCU) School of Dentistry, Department of Oral and Craniofacial Molecular Biology, Richmond, VA 23298, USA.
- VCU Massey Cancer Center, Richmond, VA 23298, USA.
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Laytragoon Lewin N, Lewin F, Andersson BÅ, Löfgren S, Rutqvist LE. The use of rapid and cost-effective blood-based biomarkers in combination with tumour TNM stage for individual head and neck cancer patient treatment selection. Med Oncol 2017; 34:63. [PMID: 28316053 PMCID: PMC5357467 DOI: 10.1007/s12032-017-0912-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Accepted: 02/28/2017] [Indexed: 01/09/2023]
Abstract
Head and neck (H&N) cancer is an aggressive disease and the incidence has increased in younger population worldwide. Tumour TNM staging is the main basis for treatment decision despite significant variation in clinical outcome. Survival time of these patients has marginally improved during the last 30 years. Various biomarkers with cumbersome analysis, high cost, time consumption and requirement of special laboratory facilities have been investigated. However, none of these biomarkers have been shown to be suitable to use for individual H&N cancer patient treatment selection in the clinic. For practical use in clinical settings, the given biomarkers must be simple to analyse, rapid, cost effective and available in routine laboratories. With this intension, we suggested the combination of standard TNM staging and biomarkers associated with inflammation such as neutrophils, neutrophil to lymphocyte ratio, plasma C-reactive protein or plasma tumour necrosis factor alpha (TNFa) and single-nucleotide polymorphism in TNFa rs1800629 using blood-based analysis. The optimal treatment outcome of H&N cancer by using combination of TNM stage and these blood-based biomarkers for individual patient selection need further investigation.
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Affiliation(s)
- Nongnit Laytragoon Lewin
- Division of Medical Diagnostic, Ryhov Hospital, 55322, Jönköping, Sweden. .,Department of Clinical and Experimental Medicine, Linköping University, 58185, Linköping, Sweden.
| | - Freddi Lewin
- Department of Oncology, Ryhov Hospital, 55322, Jönköping, Sweden
| | - Bengt-Åke Andersson
- Division of Medical Diagnostic, Ryhov Hospital, 55322, Jönköping, Sweden.,Department of Clinical and Experimental Medicine, Linköping University, 58185, Linköping, Sweden
| | - Sture Löfgren
- Division of Medical Diagnostic, Ryhov Hospital, 55322, Jönköping, Sweden
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Abstract
Human papillomaviruses (HPVs) are a necessary cause of anogenital squamous cell carcinomas (SCC) and a subgroup of head and neck SCC, i.e., those originating in the oropharynx. The key events in high-risk HPV (HRHPV)-associated neoplastic progression include persistent infection, deregulated expression of virus early genes in basal epithelial cells, local immune suppression and the accumulation of chromosomal alterations. Evidence for these events particularly comes from studies of uterine cervical carcinogenesis; primary premalignant HRHPV-positive lesions of the head and neck mucosa are seldomly detected. Integration of virus DNA into host chromosomes is considered an important driver of carcinogenesis and observed in 40 up to 90 % of uterine cervical SCC (UCSCC) and oropharyngeal SCC (OPSCC), dependent on the integration detection method used and HRHPV type. In OPSCC, > 90 % HPV-positive tumors are infected with HPV16. Ten up to 60 % of HPV-positive tumors thus contain extrachromosomal (episomal) virus. In this chapter, causes and consequences of HPV integration are summarized from the literature, with special focus on the site of HPV integration in the cellular genome, and its effect on expression of viral oncogenes (particularly E6 and E7), on human (tumor) gene expression and on deregulation of cell proliferation, apoptosis and cell signaling pathways. Also data on DNA methylation, viral load and clinical outcome in relation to HPV integration are provided.
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Affiliation(s)
- Ernst Jan M Speel
- Unit Molecular Oncopathology & Diagnostics, Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ, Maastricht, The Netherlands.
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Treatment outcomes in veterans with HPV-positive head and neck cancer. Am J Otolaryngol 2017; 38:188-192. [PMID: 28342482 DOI: 10.1016/j.amjoto.2017.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 01/16/2017] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Head and neck squamous cell carcinoma (HNSCC) caused by the human papilloma virus (HPV) has an improved prognosis relative to HPV-negative tumors. Patients with HPV-positive disease may benefit from different treatment modalities in order to optimize survival and quality of life. We sought to investigate HPV-positive HNSCC within the military veteran population, and analyze the role of treatment modality in outcomes of patients with HPV-positive and HPV-negative tumors. METHODS Patients diagnosed with HNSCC between January 1, 2010 and December 31, 2014 at one regional veterans health center were retrospectively examined. Pathologic specimens underwent testing for HPV subtype and p16 expression. Demographic and clinical factors, including treatment modality, were analyzed for their impact on the primary outcome of overall survival. RESULTS There were 209 patients with primary tumor sites including larynx (25.4%), oral tongue (19.6%), oral cavity (13.4%), oropharynx (17.2%), tonsil (17.2%), unknown primary (2.9%), nasopharynx (1.9%), and multiple sites (2.4%). Patients had HPV-positive (n=82, 39.2%), HPV-negative (n=89, 42.6%) or unknown HPV status (n=38, 18.2%). Primary treatment modalities were chemoradiation (n=124, 59.3%), surgery (n=39, 18.7%), radiation therapy (n=37, 17.7%), or no treatment (n=9, 4.3%). Survival analysis with Cox proportional hazards model demonstrated significant associations with T classification (T4 3.61, P=0.005), N classification (N3 3.52, P=0.0159), M classification (M1 2.8, P=0.0209), and HPV status (HPV-positive 0.43, P=0.0185), but no relation with primary treatment modality (primary surgery vs. primary chemoradiation 1.01, P=0.9718). CONCLUSION HPV-positive HNSCC in the veteran population has a significantly improved prognosis relative to similarly staged patients with HPV-negative disease. This study demonstrates that the primary treatment modality - chemoradiation, radiation therapy, or surgery - does not impact overall survival among veterans with HPV-positive HNSCC.
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36
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Lindsay C, Seikaly H, Biron VL. Epigenetics of oropharyngeal squamous cell carcinoma: opportunities for novel chemotherapeutic targets. J Otolaryngol Head Neck Surg 2017; 46:9. [PMID: 28143553 PMCID: PMC5282807 DOI: 10.1186/s40463-017-0185-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 01/20/2017] [Indexed: 12/29/2022] Open
Abstract
Epigenetic modifications are heritable changes in gene expression that do not directly alter DNA sequence. These modifications include DNA methylation, histone post-translational modifications, small and non-coding RNAs. Alterations in epigenetic profiles cause deregulation of fundamental gene expression pathways associated with carcinogenesis. The role of epigenetics in oropharyngeal squamous cell carcinoma (OPSCC) has recently been recognized, with implications for novel biomarkers, molecular diagnostics and chemotherapeutics. In this review, important epigenetic pathways in human papillomavirus (HPV) positive and negative OPSCC are summarized, as well as the potential clinical utility of this knowledge.This material has never been published and is not currently under evaluation in any other peer-reviewed publication.
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Affiliation(s)
- Cameron Lindsay
- Faculty of Medicine and Dentistry, Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alberta, 1E4.34 WMC, 8440 112 Street, Edmonton, AB, T6G 2B7, Canada
| | - Hadi Seikaly
- Faculty of Medicine and Dentistry, Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alberta, 1E4.34 WMC, 8440 112 Street, Edmonton, AB, T6G 2B7, Canada
| | - Vincent L Biron
- Faculty of Medicine and Dentistry, Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Alberta, 1E4.34 WMC, 8440 112 Street, Edmonton, AB, T6G 2B7, Canada.
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Khanal S, Trainor PJ, Zahin M, Ghim SJ, Joh J, Rai SN, Jenson AB, Shumway BS. Histologic variation in high grade oral epithelial dysplasia when associated with high-risk human papillomavirus. Oral Surg Oral Med Oral Pathol Oral Radiol 2017; 123:566-585. [PMID: 28407985 DOI: 10.1016/j.oooo.2017.01.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 01/05/2017] [Accepted: 01/10/2017] [Indexed: 01/05/2023]
Abstract
OBJECTIVES Reported cytologic alterations associated with high-risk human papillomavirus (HR-HPV) in oral epithelial dysplasia (HPV-OED) need further characterization. STUDY DESIGN Archival cases of high-grade oral epithelial dysplasia (hgOED) (N = 38) were assigned a cytologic score (CS) based on the average number of mitotic, karyorrhectic, and apoptotic cells per high-power field. Three groups were then generated on the basis of increasing CS: Focal (group 1, N = 14), Intermediate (group 2, N = 12), and Diffuse (group 3, N = 12). Polymerase chain reaction-based HPV genotyping and p16 immunohistochemistry were performed. RESULTS HR-HPV was found significantly more in group 3 (83.3%) compared with groups 1 and 2 (group 1&2; 42.9% and 41.7%, respectively; P = .047). HPV16 predominated in HR-HPV-positive cases (90.5%). By location, the tongue or the floor of mouth was associated with all groups (P = .04). Increasing CS was associated with a slightly younger age (P = .04) and increased expression of p16 (P = .005). CS and p16 expression were not sensitive but were highly specific predictors for HR-HPV presence. Based on limited follow-up information, HPV-OED does not differ in clinical aggressiveness compared with conventional OED. CONCLUSIONS Increased CS in hgOED is strongly associated with HR-HPV (mostly HPV16) and p16 expression. CS and p16 expression are specific predictors of HR-HPV presence. Further molecular study and long-term follow-up of HPV-OED are needed.
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Affiliation(s)
- Sujita Khanal
- James Graham Brown Cancer Center, Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY, USA
| | - Patrick J Trainor
- Research Associate, Biostatistics Shared Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Maryam Zahin
- Postdoctoral Associate, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Shin-Je Ghim
- Assistant Professor, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Joongho Joh
- Assistant Professor, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Shesh N Rai
- Professor, Wendell Cherry Chair in Clinical Trial Research; Director, Biostatistics Shared Facility, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Alfred Bennett Jenson
- Senior scientist, Professor of Vaccinology, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
| | - Brian S Shumway
- Associate Professor, Oral and Maxillofacial Pathology, Department of Surgical and Hospital Dentistry, University of Louisville School of Dentistry, Louisville, KY, USA.
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Pierssens DDCG, Borgemeester MC, van der Heijden SJH, Peutz-Kootstra CJ, Ruland AM, Haesevoets AM, Kessler PAWH, Kremer B, Speel EJM. Chromosome instability in tumor resection margins of primary OSCC is a predictor of local recurrence. Oral Oncol 2017; 66:14-21. [PMID: 28249643 DOI: 10.1016/j.oraloncology.2016.12.029] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Revised: 12/08/2016] [Accepted: 12/28/2016] [Indexed: 11/17/2022]
Abstract
BACKGROUND The local recurrence rate in oral squamous cell cancer (OSCC) hardly decreases. This is partly due to the presence of (pre)malignant cells in the remaining tissue after resection, that may lead to the development of a new tumor in time. Detection of histologically (pre)malignant cells in the tumor resection margins should predict these patients at risk for recurrence, however this appears to be difficult in routine practice. Purpose of this study was to apply easy-to-use molecular tests for more accurate detection of (pre)malignant cells in histopathologically tumor-free margins, to improve diagnosis of patients at risk. METHODS 42 patients with firstly diagnosed, radically resected primary OSCC with histopathologically confirmed tumor-free resection margins (treated between 1994 and 2003) were included. Inclusion criteria comprised of follow-up ⩾5years, and radical surgery without postoperative treatment. Formalin-fixed paraffine-embedded tissue sections of 42 tumors, 290 resection margins, and 11 recurrences were subjected to fluorescence in situ hybridization (FISH) to examine chromosome 1 and 7 copy number variations (CNV), and to p53 immunohistochemistry (IHC). RESULTS 11 out of the 42 patients developed a local recurrence within 5years. FISH analysis showed that nine of eleven recurrences exhibited CI in at least one of the resection margins (p=0.008). P53 overexpression and routine histopathologic classification were not correlated with recurrent disease. The presence of CI in the resection margins revealed a significantly worse progression-free survival (log-rank p=0.012). CONCLUSIONS CI in the resection margins of OSCC can reliably identify patients at risk for developing a local recurrence.
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Affiliation(s)
- Damiana D C G Pierssens
- Department of Oral and Craniomaxillofacial Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
| | - Maarten C Borgemeester
- Department of Otorhinolaryngology, Head & Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Stijn J H van der Heijden
- Department of Otorhinolaryngology, Head & Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Carine J Peutz-Kootstra
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Andrea M Ruland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Annick M Haesevoets
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Peter A W H Kessler
- Department of Oral and Craniomaxillofacial Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Bernd Kremer
- Department of Otorhinolaryngology, Head & Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Ernst-Jan M Speel
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands
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Expression of Cell Cycle-associated Proteins p53, pRb, p16, p27, and Correlation With Survival: A Comparative Study on Oral Squamous Cell Carcinoma and Verrucous Carcinoma. Appl Immunohistochem Mol Morphol 2016; 24:193-200. [PMID: 26447892 DOI: 10.1097/pai.0000000000000179] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Verrucous carcinoma (VC) is a well-differentiated form of squamous cell carcinoma (SCC) with better prognosis. Differences in molecular pathogenesis between the 2 have not been well-characterized. We conducted this study to evaluate immunohistochemical expression of cell-cycle regulatory proteins p53, pRb, p16, and p27 in SCC and VC, compare the expression in these 2 neoplasms, and assess if these markers have any diagnostic or prognostic value. Sixty cases of SCC with and without lymph node metastasis and 31 cases of VC were studied. Immunohistochemical analysis for p53, pRb, p16, and p27 was performed and the results were analyzed. SCC was most frequent in tongue (52%), whereas VC in buccal mucosa (81%). Mean age of SCC patients was significantly lower than in VC. Majority of SCCs were in stage III and IV (63%), whereas VCs were in stage I and II (84%). p53 immunopositivity was more frequent in SCC (65%) than in VC (23%) (P≤0.001). VC had lower p53 as compared with well-differentiated SCC and SCC without lymph node metastasis. No significant difference was seen in pRb, p16, and p27 expression. Disease-free survival (DFS) at 1 year for SCC was 57% whereas it was 80% for VC (P=0.02). DFS and overall survival of SCC correlated with nodal status and stage; cell-cycle-associated protein expression had no association with DFS. To conclude, p53 immunoexpression differs in SCC and VC, suggesting different pathogenesis, and it may have some utility as an adjunct to morphology to differentiate between the 2. Expression of cell-cycle-associated proteins does not influence survival in SCC.
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Worsham MJ, Chen KM, Datta I, Stephen JK, Chitale D, Gothard A, Divine G. The biological significance of methylome differences in human papilloma virus associated head and neck cancer. Oncol Lett 2016; 12:4949-4956. [PMID: 28101231 PMCID: PMC5228097 DOI: 10.3892/ol.2016.5303] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Accepted: 08/26/2016] [Indexed: 01/02/2023] Open
Abstract
In recent years, studies have suggested that promoter methylation in human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) has a mechanistic role and has the potential to improve patient survival. The present study aimed to replicate key molecular findings from previous analyses of the methylomes of HPV positive and HPV negative HNSCC in an independent cohort, to assess the reliability of differentially methylated markers in HPV-associated tumors. HPV was measured using real-time quantitative PCR and the biological significance of methylation differences was assessed by Ingenuity Pathway Analysis (IPA). Using an identical experimental design of a 450K methylation platform, 7 of the 11 genes were detected to be significantly differentially methylated and all 11 genes were either hypo- or hypermethylated, which was in agreement with the results of a previous study. IPA's enriched networks analysis identified one network with msh homeobox 2 (MSX2) as a central node. Locally dense interactions between genes in networks tend to reflect significant biology; therefore MSX2 was selected as an important gene. Sequestration in the top four canonical pathways was noted for 5-hydroxytryptamine receptor 1E (serotonin signaling), collapsin response mediator protein 1 (semaphorin signaling) and paired like homeodomain 2 (bone morphogenic protein and transforming growth factor-β signaling). Placement of 9 of the 11 genes in highly ranked pathways and bionetworks identified key biological processes to further emphasize differences between HNSCC HPV positive and negative pathogenesis.
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Affiliation(s)
- Maria J Worsham
- Department of Otolaryngology/Head and Neck Research, Henry Ford Hospital, Detroit, MI 48202, USA
| | - Kang Mei Chen
- Department of Otolaryngology/Head and Neck Research, Henry Ford Hospital, Detroit, MI 48202, USA
| | - Indrani Datta
- Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI 48202, USA
| | - Josena K Stephen
- Department of Otolaryngology/Head and Neck Research, Henry Ford Hospital, Detroit, MI 48202, USA
| | - Dhananjay Chitale
- Department of Pathology, Henry Ford Hospital, Detroit, MI 48202, USA
| | | | - George Divine
- Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI 48202, USA
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41
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Wang Z, Xia RH, Ye DX, Li J. Human Papillomavirus 16 Infection and TP53 Mutation: Two Distinct Pathogeneses for Oropharyngeal Squamous Cell Carcinoma in an Eastern Chinese Population. PLoS One 2016; 11:e0164491. [PMID: 27749915 PMCID: PMC5066983 DOI: 10.1371/journal.pone.0164491] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 09/26/2016] [Indexed: 12/16/2022] Open
Abstract
Objectives To investigate the clinicopathological characteristics, human papillomavirus (HPV) infection, p53 expression, and TP53 mutations in oropharyngeal squamous cell carcinoma (OPSCC) and determine their utility as prognostic predictors in a primarily eastern Chinese population. Methods The HPV infection status was tested via p16INK4A immunohistochemistry and validated using PCR, reverse blot hybridization and in situ hybridization (ISH) in 188 OPSCC samples. p53 expression levels and TP53 gene mutations were assessed through immunohistochemistry and sequencing, respectively. Clinicopathological characteristics and follow-up information were collected. Overall survival was estimated using the Log-rank test. Results Overall, 22 of the 188 OPSCC samples were associated with HPV infection. HPV16 was identified in all 22 samples, whereas no samples were positive for HPV18. All 22 HPV-associated OPSCC samples were p53 negative and lacked TP53 mutations. HPV16 positivity, female patients, non-smokers, and patients with histological grade I and stage N0 diseases showed better overall survival (p = 0.009, 0.003, 0.048, 0.009, and 0.004, respectively). No significant differences in overall survival between smoking and non-smoking patients were observed in the HPV-associated OPSCC group. Patients without mutations in TP53 exons 5–8 had better prognoses (p = 0.031) among the 43 sequenced specimens. Multivariate analysis indicated that HPV16 infection status (p = 0.011), histological grade (p = 0.017), and N stage (p = 0.019) were independent prognostic factors for patients with OPSCC. Conclusions Distinct from the situation in Europe and America, for the patients with OPSCC in this study, HPV16 infection was relatively low, although it was still the most important independent prognostic predictor for the disease. In addition to the high smoking and drinking rate in this population, HPV16 infection and TP53 dysfunction appear to be two distinct pathogens for OPSCC patients in the eastern Chinese population.
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Affiliation(s)
- Zhen Wang
- Department of Oral Pathology, ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, P. R. China
| | - Rong-Hui Xia
- Department of Oral Pathology, ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, P. R. China
| | - Dong-Xia Ye
- Department of Oral Maxillofacial Surgery, ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, P. R. China
| | - Jiang Li
- Department of Oral Pathology, ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, P. R. China
- * E-mail:
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42
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Ou P, Gear K, Rahnama F, Thomas S, Nagappan R, Kee D, Waldvogel-Thurlow S, Jain R, McIvor N, Izzard M, Douglas R. Human papillomavirus and oropharyngeal squamous cell carcinoma: a New Zealand cohort study. ANZ J Surg 2016; 88:E278-E283. [DOI: 10.1111/ans.13759] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 04/04/2016] [Accepted: 07/18/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Peter Ou
- Department of Surgery; The University of Auckland; Auckland New Zealand
| | - Kim Gear
- Department of Oto-rhinolaryngology; Head and Neck Surgery, Auckland District Health Board; Auckland New Zealand
| | - Fahimeh Rahnama
- Department of Virology and Anatomical Pathology; LabPLUS, Auckland District Health Board; Auckland New Zealand
| | - Stephen Thomas
- Department of Virology and Anatomical Pathology; LabPLUS, Auckland District Health Board; Auckland New Zealand
| | - Radhika Nagappan
- Department of Virology and Anatomical Pathology; LabPLUS, Auckland District Health Board; Auckland New Zealand
| | - Dennis Kee
- Department of Virology and Anatomical Pathology; LabPLUS, Auckland District Health Board; Auckland New Zealand
| | | | - Ravi Jain
- Department of Surgery; The University of Auckland; Auckland New Zealand
| | - Nick McIvor
- Department of Oto-rhinolaryngology; Head and Neck Surgery, Auckland District Health Board; Auckland New Zealand
| | - Mark Izzard
- Department of Oto-rhinolaryngology; Head and Neck Surgery, Auckland District Health Board; Auckland New Zealand
| | - Richard Douglas
- Department of Surgery; The University of Auckland; Auckland New Zealand
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43
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Liu H, Li J, Zhou Y, Hu Q, Zeng Y, Mohammadreza MM. Human papillomavirus as a favorable prognostic factor in a subset of head and neck squamous cell carcinomas: A meta-analysis. J Med Virol 2016; 89:710-725. [PMID: 27575972 DOI: 10.1002/jmv.24670] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 08/22/2016] [Accepted: 08/27/2016] [Indexed: 12/24/2022]
Abstract
Many epidemical and biological studies have proposed that human papillomavirus (HPV), primarily high-risk HPV16/18, is an etiological factor for a subset of head and neck (HN) cancers. On that premise, we systematically reviewed relevant articles and improved the understanding of HPV-related cancers. This article comprehensively described the characteristics of HPV-associated HN tumors according to demography, histopathology, molecular biology, and prognosis. Meta-analyses were conducted to combine the studies that reported the association between HPV status and these variables using Rev Man 5.0. The pooled results showed that HPV-positive tumors were not only poorly differentiated (OR = 2.77, 95% CI: 2.3-3.32) and smaller (OR = 2.21, 95% CI: 1.75-2.8) but were also strongly associated with oropharynx (OR = 5.8, 95% CI: 4.01-8.38) and node involvement (OR = 2.77, 95% CI: 2.3-3.32). HPV-related tumors showed significantly more p16 overexpression (OR = 34.55, 95% CI: 20.91-57.09) and less TP53 mutations (OR = 0.27, 95% CI: 0.18-0.41) than HPV-negative tumors. The patients with HPV-positive cancers had different clinical behaviors, such as a reduced risks of death (HR = 0.32, 95% CI: 0.29-0.36). This study supported the view point that HPV is a favorable indicator of prognosis and that HPV-related HN tumors are distinct from traditional tumors. This etiological relationship could impact future strategies of diagnosis, prevention, therapy, and prognosis for this subset of patients. J. Med. Virol. 89:710-725, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Hongwei Liu
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC), Chengdu, China.,Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China
| | - Jintao Li
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China.,Hubei Key Laboratory of Medical Information Analysis & Tumor Diagnosis and Treatment, Hubei, China
| | - Yubai Zhou
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China
| | - Qin Hu
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China
| | - Yi Zeng
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China.,National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, and State Key Laboratory for Infectious Disease Prevention and Control, Beijing, China
| | - Mohammadzad Mehryar Mohammadreza
- Beijing Key Laboratory of Environmental and Viral Oncology, College of Life Science and Bio-Engineering, Beijing University of Technology, Beijing, China.,Hubei Key Laboratory of Medical Information Analysis & Tumor Diagnosis and Treatment, Hubei, China
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Low GM, Thylur DS, Yamamoto V, Sinha UK. The effect of human papillomavirus on DNA repair in head and neck squamous cell carcinoma. Oral Oncol 2016; 61:27-30. [PMID: 27688101 DOI: 10.1016/j.oraloncology.2016.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Revised: 08/02/2016] [Accepted: 08/05/2016] [Indexed: 02/08/2023]
Abstract
Much of the current literature regarding the molecular pathophysiology of human papillomavirus (HPV) in head and neck squamous cell carcinoma (HNSCC) has focused on the virus's effect on cell cycle modulation and cell proliferation. A second mechanism of pathogenicity employed by HPV, dysregulation of cellular DNA repair processes, has been more sparsely studied. The purpose of this review is to describe current understanding about the effect of HPV on DNA repair in HNSCC, taking cues from cervical cancer literature. HPV affects DNA-damage response pathways by interacting with many proteins, including ATM, ATR, MRN, γ-H2AX, Chk1, Chk2, p53, BRCA1, BRCA2, RAD51, Rb-related proteins 107 and 130, Tip60, and p16INK4A. Further elucidation of these pathways could lead to development of targeted therapies and improvement of current treatment protocols.
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Affiliation(s)
- Garren M Low
- USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
| | - David S Thylur
- USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
| | - Vicky Yamamoto
- USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
| | - Uttam K Sinha
- USC Tina and Rick Caruso Department of Otolaryngology-Head & Neck Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
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Baboci L, Holzinger D, Boscolo-Rizzo P, Tirelli G, Spinato R, Lupato V, Fuson R, Schmitt M, Michel A, Halec G, Da Mosto MC, Pawlita M, Del Mistro A. Low prevalence of HPV-driven head and neck squamous cell carcinoma in North-East Italy. PAPILLOMAVIRUS RESEARCH 2016; 2:133-140. [PMID: 29074172 PMCID: PMC5886905 DOI: 10.1016/j.pvr.2016.07.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 07/14/2016] [Accepted: 07/14/2016] [Indexed: 02/03/2023]
Abstract
Objectives To investigate the frequency of Human papillomavirus (HPV)-driven head and neck squamous cell carcinoma (HNSCC) among patients living in North-East Italy, by assessing HPV-DNA positivity in all tumors and additional markers whenever possible. Material and methods HPV types, viral load, viral RNA, HPV16/18 E6 protein and p16INK4a and pRb expression were determined in primary tumor tissues from 247 HNSCC patients. Tumor-specific HPV seropositivity was analyzed in 102 patients. Results Tumor HPV-DNA prevalence was 8.5% overall (21/247) and 27% in oropharynx (17/63). HPV16 accounted for 95% of all HPV types found. Among HPV-DNA+ tumors, type-concordant HPV E6*I RNA prevalence was 79%. HPV DNA+ RNA+ tumors showed high viral load, up-regulated p16INK4a, down-regulated pRb and presence of HPV16 E6 protein. Eight cases showed tumor-specific HPV seropositivity, all type-concordant with the tumor. Tumors were defined as HPV-driven when positive for HPV-DNA plus 2 additional HPV transformation-related markers. Conclusion Relative prevalence of HPV-driven tumors (14 HPV16, 1 HPV58) was 6% overall and 20% among oropharyngeal cancers. In the oropharynx the HPV-driven group showed a trend for better survival versus the HPV-negative group. The relative prevalence of HPV-driven oropharyngeal cancer is low in North-East Italy as compared to Western and Northern Europe.
HPV DNA alone is not sufficient to demonstrate causality in HNSCC. Additional transformation markers are needed to correctly identify HPV-driven tumors. HPV prevalence in HNSCC shows large geographical variation, even within Europe. Few small studies investigated the relative prevalence of HPV in HNSCC in Italy. In North-East Italy 6% of HNSCC and 20% of OPSCC are HPV-driven.
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Affiliation(s)
- Lorena Baboci
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany; Department of Surgery, Oncology and Gastroenterology, University of Padua, Oncology and Immunology Section, Via Gattamelata 64, 35128 Padua, Italy.
| | - Dana Holzinger
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
| | - Paolo Boscolo-Rizzo
- Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, School of Medicine, Treviso Regional Hospital, P.le Ospedale 1, 31100 Treviso, Italy.
| | - Giancarlo Tirelli
- Head and Neck Department, Hospital of Cattinara, University of Trieste, Strada di Fiume 447, 34149 Trieste, Italy.
| | - Roberto Spinato
- Venetian Department of Otolaryngology, Ospedale dell'Angelo, Via Paccagnella 11, 30174 Venezia Mestre, Italy.
| | - Valentina Lupato
- Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, School of Medicine, Treviso Regional Hospital, P.le Ospedale 1, 31100 Treviso, Italy.
| | - Roberto Fuson
- Venetian Department of Otolaryngology, Ospedale dell'Angelo, Via Paccagnella 11, 30174 Venezia Mestre, Italy.
| | - Markus Schmitt
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
| | - Angelika Michel
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
| | - Gordana Halec
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
| | - Maria Cristina Da Mosto
- Department of Neurosciences, ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, School of Medicine, Treviso Regional Hospital, P.le Ospedale 1, 31100 Treviso, Italy.
| | - Michael Pawlita
- Division of Molecular Diagnostics of Oncogenic Infections, Research Program Infection and Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
| | - Annarosa Del Mistro
- Veneto Institute of Oncology IOV - IRCCS, Immunology and Molecular Oncology Unit, Via Gattamelata, 64, 35128 Padua, Italy.
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Zhang W, Edwards A, Fang Z, Flemington EK, Zhang K. Integrative Genomics and Transcriptomics Analysis Reveals Potential Mechanisms for Favorable Prognosis of Patients with HPV-Positive Head and Neck Carcinomas. Sci Rep 2016; 6:24927. [PMID: 27108969 PMCID: PMC4842993 DOI: 10.1038/srep24927] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 04/07/2016] [Indexed: 12/19/2022] Open
Abstract
Patients with HPV-positive head neck squamous cell carcinomas (HNSCC) usually have a better prognosis than the HPV-negative cases while the underlying mechanism remains far from being well understood. We investigated this issue by an integrative analysis of clinically-annotated multi-omics HNSCC data released by the Cancer Genome Atlas. As confirmatory results, we found: (1) Co-occurrence of mutant TP53 and HPV infection was rare; (2) Regardless of HPV status, HNSCCs of wild-type TP53 implied a good survival chance for patients and had fewer genome-wide somatic mutations than those with a mutation burden on the gene. Our analysis further led to some novel observations. They included: (1) The genes involved in “DNA mismatch repair” pathway were up-regulated in HPV-positive tumors compared to normal tissue samples and HPV-negative cases, and thus constituted a strong predictive signature for the identification of HPV infection; (2) HPV infection could disrupt some regulatory miRNA-mRNA correlations operational in the HPV-negative tumors. In light of these results, we proposed a hypothesis for the favorable clinical outcomes of HPV-positive HNSCC patients. That is, the replication of HPV genome and/or its invasion into the genomes of cancer cells may enhance DNA repair mechanisms, which in turn limit the accumulation of lethal somatic mutations.
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Affiliation(s)
- Wensheng Zhang
- Department of Computer Science, Xavier University of Louisiana, 1 Drexel Drive, New Orleans LA 70125, USA
| | - Andrea Edwards
- Department of Computer Science, Xavier University of Louisiana, 1 Drexel Drive, New Orleans LA 70125, USA
| | - Zhide Fang
- Biostatistics Program, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA
| | - Erik K Flemington
- Tulane Health Sciences Center, Tulane Cancer Center, Tulane University, 1700 Tulane Ave, New Orleans, LA 70112, USA
| | - Kun Zhang
- Department of Computer Science, Xavier University of Louisiana, 1 Drexel Drive, New Orleans LA 70125, USA
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Vuichoud C, Klap J, Loughlin KR. The Emerging Role and Promise of Biomarkers in Penile Cancer. Urol Clin North Am 2016; 43:135-43. [PMID: 26614036 DOI: 10.1016/j.ucl.2015.08.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Penile cancer is a rare malignancy, which can be a source of devastating psychosexual distress because of its implication on sexual function and self-image. Current penile staging relies on invasive techniques and is often inaccurate. The authors review the promising biomarkers currently under investigation and their application to the staging and prognosis of penile cancer. Further development of such biomarkers provides the potential of improved clinical management of this disease.
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Affiliation(s)
- Camille Vuichoud
- Division of Urology, Brigham and Women's Hospital, Harvard Medical School, 45 Francis Street, Boston, MA 02115, USA
| | - Julia Klap
- Division of Urology, Brigham and Women's Hospital, Harvard Medical School, 45 Francis Street, Boston, MA 02115, USA
| | - Kevin R Loughlin
- Division of Urology, Brigham and Women's Hospital, Harvard Medical School, 45 Francis Street, Boston, MA 02115, USA.
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48
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Abstract
The most common malignancy to involve the oral cavity and oropharynx is squamous cell carcinoma (SCC). Because these oral cancers share an origin from the squamous epithelium, the pathology of oral SCC might be expected to be uniform and its diagnosis repetitive. In reality, the morphologic diversity in SCC, along with the propensity for reactive processes of the oral cavity to mimic SCC histologically, renders its diagnosis one of the more challenging in surgical pathology. This article discusses variants of oral and oropharyngeal SCC and highlights those features that help distinguish human papillomavirus-related from human papillomavirus-unrelated SCC.
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49
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Abstract
The nasal cavity and paranasal sinuses occupy the top of the upper respiratory tract and form pneumatic spaces connected with the atmosphere. They are located immediately beneath the base of the cranium, where crucial vital structures are harbored. From this region, very much exposed to airborne agents, arise some of the more complex and rare benign and malignant lesions seen in humans, whose difficulties in interpretation make this remarkable territory one of the most challenging in the practice of surgical pathology. Contents of this chapter cover inflammations and infections, polyps and pseudotumors, fungal and midfacial destructive granulomatous lesions, as well as benign, borderline, and malignant neoplasms. Among the neoplasms, emphasis is made on those entities characteristic or even unique for the sinonasal region, such as Schneiderian papillomas, glomangiopericytoma, intestinal- and non-intestinal-type adenocarcinomas, olfactory neuroblastoma, nasal-type NK-/T-cell lymphoma, and teratocarcinosarcoma. Moreover, recently recognized entities involving this territory, i.e., HPV-related non-keratinizing carcinoma, NUT carcinoma, and SMARCB1-deficient basaloid carcinoma, are also discussed in the light of their specific molecular findings. Furthermore, the text is accompanied by numerous classical and recent references, several tables, and 100 illustrations.
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Affiliation(s)
- Antonio Cardesa
- University of Barcelona, Anatomic Pathology Hospital Clínic University of Barcelona, Barcelona, Spain
| | - Pieter J. Slootweg
- Radboud Univ Nijmegen Medical Center, Pathology Radboud Univ Nijmegen Medical Center, Nijmegen, The Netherlands
| | - Nina Gale
- University of Ljubljana,, Institute of Pathology, Faculty of Medic University of Ljubljana,, Ljublijana, Slovenia
| | - Alessandro Franchi
- University of Florence, Dept of Surg & Translational Medicine University of Florence, Florence, Italy
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van Monsjou H, Schaapveld M, van den Brekel M, Balm A. The epidemiology of head and neck squamous cell carcinoma in The Netherlands during the era of HPV-related oropharyngeal squamous cell carcinoma. Is there really evidence for a change? Oral Oncol 2015. [DOI: 10.1016/j.oraloncology.2015.06.011] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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