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Khan A, Pillay M, Bipath R, Msimang M, Harry J, Sibiya AL, Msomi N. Evolution of testing for the diagnosis of human papillomavirus (HPV) status in head and neck squamous cell carcinoma: Where from and where to? Oral Oncol 2025; 162:107208. [PMID: 39899908 DOI: 10.1016/j.oraloncology.2025.107208] [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: 08/04/2024] [Revised: 01/17/2025] [Accepted: 01/25/2025] [Indexed: 02/05/2025]
Abstract
Human papillomavirus (HPV) is causally associated with head and neck squamous cell carcinomas with the strongest association in the oropharynx. HPV-associated oropharyngeal carcinomas have a different pathogenesis with distinct clinical features and better prognosis than HPV-negative oropharyngeal carcinomas which impacts staging and prognosis. It is, therefore, of clinical significance to accurately determine the HPV status, particularly in oropharyngeal carcinomas. In this review, the different test methods that are used for characterizing HPV status in head and neck squamous cell carcinomas, both conventional methods (p16 immunohistochemistry, HPV DNA in-situ hybridization, HPV DNA PCR, HPV E6/E7 mRNA RT-PCR, HPV RNA in-situ hybridization) as well as emerging novel approaches (HPV circulating tumour DNA, HPV16 E6 antibodies, oral HPV DNA/mRNA PCR), are discussed. Currently, a combined testing approach is favoured, using a sequential strategy of screening with p16 immunohistochemistry and confirming with HPV DNA PCR. HPV RNA in-situ hybridization could potentially serve as a single test owing to its good sensitivity and specificity. The use of liquid biopsies is gaining momentum with HPV circulating tumour DNA as the frontrunner in demonstrating promising clinical utility for early detection in HPV-associated oropharyngeal carcinomas. HPV16 E6 antibodies and oral HPV DNA PCR has potential utility as adjunct tests to aid diagnosis. In this rapidly evolving HPV testing landscape, we as clinicians and laboratorians must evolve and advocate for access to cost-effective accurate HPV testing globally.
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Affiliation(s)
- Aabida Khan
- Department of Virology, National Health Laboratory Service and School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa.
| | - Melendhran Pillay
- Department of Virology, National Health Laboratory Service and School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Rishan Bipath
- Department of Otorhinolaryngology, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Mpumelelo Msimang
- Department of Anatomical Pathology, National Health Laboratory Service and School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Jason Harry
- Department of Anatomical Pathology, National Health Laboratory Service and School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Andile Lindokuhle Sibiya
- Department of Otorhinolaryngology, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Nokukhanya Msomi
- Department of Virology, National Health Laboratory Service and School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
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2
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Kusters JMA, Diergaarde B, Ness A, van der Loeff MFS, Heijne JCM, Schroeder L, Hueniken K, McKay JD, Macfarlane GJ, Lagiou P, Lagiou A, Polesel J, Agudo A, Alemany L, Ahrens W, Healy CM, Conway DI, Robinson M, Canova C, Holcátová I, Richiardi L, Znaor A, Pring M, Thomas S, Hayes DN, Liu G, Hung RJ, Brennan P, Olshan AF, Virani S, Waterboer T. Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex. Int J Cancer 2024; 154:389-402. [PMID: 37694289 PMCID: PMC11552661 DOI: 10.1002/ijc.34710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/17/2023] [Accepted: 07/31/2023] [Indexed: 09/12/2023]
Abstract
A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.
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Affiliation(s)
- Johannes M. A. Kusters
- Centre for Infectious Diseases Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
- Institute for Infection and Immunity (AII), Amsterdam UMC, Amsterdam, The Netherlands
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Brenda Diergaarde
- School of Public Health, University of Pittsburgh and UPMC Hillman Cancer Centre, Pittsburgh, Pennsylvania, USA
| | - Andrew Ness
- NIHR Bristol Biomedical Research Centre, Weston NHS Foundation Trust, University of Bristol, Bristol, UK
- Bristol Dental School, University of Bristol, Bristol, UK
| | - Maarten F. Schim van der Loeff
- Institute for Infection and Immunity (AII), Amsterdam UMC, Amsterdam, The Netherlands
- Department of Infectious Diseases, Public Health Service of Amsterdam, Amsterdam, The Netherlands
| | - Janneke C. M. Heijne
- Centre for Infectious Diseases Control, National Institute for Public Health and the Environment, Bilthoven, The Netherlands
- Department of Social Medicine, Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht, The Netherlands
| | - Lea Schroeder
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katrina Hueniken
- Princess Margaret Cancer Centre, Temerty School of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - James D. McKay
- Genomic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - Gary J. Macfarlane
- Epidemiology Group, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK
| | - Pagona Lagiou
- School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Areti Lagiou
- School of Public Health, University of West Attica, Athens, Greece
| | - Jerry Polesel
- Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Italy
| | - Antonio Agudo
- Unit of Nutrition and Cancer, Catalan Institute of Oncology – ICO, L’Hospitalet de Llobregat, Spain
- Nutrition and Cancer Group, Epidemiology Public Health Cancer Prevention and Palliative Care Program, Bellvitge Biomedical Research Institute – IDIBELL, L’Hospitalet de Llobregat, Spain
| | - Laia Alemany
- Nutrition and Cancer Group, Epidemiology Public Health Cancer Prevention and Palliative Care Program, Bellvitge Biomedical Research Institute – IDIBELL, L’Hospitalet de Llobregat, Spain
- Centro de Investigación Biomédica en Red: Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Madrid, Spain
| | | | | | - David I. Conway
- School of Medicine, Dentistry, and Nursing, University of Glasgow, Dublin, UK
| | - Max Robinson
- Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | | | - Ivana Holcátová
- First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University, Prague, Czech Republic
| | - Lorenzo Richiardi
- Reference Center for Epidemiology and Cancer Prevention, Piemonte, Italy
| | - Ariana Znaor
- Genomic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - Miranda Pring
- Bristol Dental School, University of Bristol, Bristol, UK
| | - Steve Thomas
- Bristol Dental School, University of Bristol, Bristol, UK
| | - D. Neil Hayes
- Division of Medical Oncology and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Geoffrey Liu
- Princess Margaret Cancer Centre, Temerty School of Medicine, University of Toronto, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
| | - Rayjean J. Hung
- Dalla Lana School of Public Health, University of Toronto, Toronto, Canada
- Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada
| | - Paul Brennan
- Genomic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - Andrew F. Olshan
- University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA
| | - Shama Virani
- Genomic Epidemiology Group, International Agency for Research on Cancer, Lyon, France
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Kuga R, Yamamoto H, Jiromaru R, Hongo T, Yasumatsu R, Matsuo M, Hashimoto K, Taniguchi M, Nakagawa T, Oda Y. HPV Infection in Squamous Cell Carcinoma of the Hypopharynx, Larynx, and Oropharynx With Multisite Involvement. Am J Surg Pathol 2023; 47:955-966. [PMID: 37357948 DOI: 10.1097/pas.0000000000002086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
The prevalence and prognostic significance of high-risk human papillomavirus (HR-HPV) have been well-established in oropharyngeal squamous cell carcinoma (OPSCC), but not in hypopharyngeal squamous cell carcinoma (HPSCC) or laryngeal squamous cell carcinoma (LSCC). Moreover, HR-HPV infection in squamous cell carcinoma with multisite involvement has not been examined. To clarify these issues, we retrospectively collected 480 invasive tumors from 467 patients with HPSCC, LSCC, or OPSCC, and comprehensively analyzed the detailed tumor localization, transcriptionally active HR-HPV infection by messenger RNA in situ hybridization, and immunohistochemical staining for p16 and Rb. HR-HPV infection was observed in 115/480 tumors (24%). Human papillomavirus (HPV)-positive cases were closely related with p16 positivity and the partial loss pattern of Rb. HR-HPV was detected in 104 of 161 tumors (64.6%) in the pure OPSCC group and only 1 of 253 tumors (0.4%) in the pure HP/LSCC group; the positive case occurred in the vocal cords. In the multisite-involving combined-type squamous cell carcinoma group, HPV infection was observed in 10/40 (25%) cases, and the 10 HPV-positive cases had OPSCC extending to the larynx or hypopharynx. Among high T-stage (T3/T4) cases of pure OPSCC, HPV-positive cases showed a better prognosis ( P =0.0144), whereas the HPV-positive combined OPSCC group did not show a better prognosis ( P =0.9428), as compared with HPV-negative counterpart. The results suggest that HR-HPV infection in pure HPSCC and LSCC may be extremely rare. HR-HPV infection seems to be present in a substantial proportion of patients with combined OPSCC and HPSCC/LSCC, but it may not improve prognosis at such advanced disease stages. Confirmation of these points awaits future studies with larger cohorts.
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Affiliation(s)
| | | | - Rina Jiromaru
- Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Takahiro Hongo
- Departments of Anatomic Pathology
- Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Ryuji Yasumatsu
- Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
- Department of Otorhinolaryngology Head and Neck Surgery, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Mioko Matsuo
- Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | - Kazuki Hashimoto
- Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
| | | | - Takashi Nakagawa
- Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka
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4
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Kejner A, Gentile C, Porterfield Z, Carroll WR, Buczek EP. Positive Deep Initial Incision Margin Affects Outcomes in TORS for HPV+ Oropharynx Cancer. Laryngoscope 2023; 133:1132-1137. [PMID: 35809041 PMCID: PMC9826797 DOI: 10.1002/lary.30275] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 04/15/2022] [Accepted: 05/28/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Evaluate the effect of initial incision margins (IIM) on clinical outcomes after transoral robotic surgery (TORS) for human papillomavirus positive (HPV+) squamous cell cancers of the oropharynx (OPSCC). METHODS Retrospective chart review of patients undergoing TORS for HPV+ OPSCC from 2007 to 2015 was performed. Overall survival (OS), disease-specific survival (DSS), recurrence, and metastases were evaluated in the context of pathology, IIM, final margins, adjuvant therapy, and patient characteristics. RESULTS Ninety-five patients with HPV+ OPSCC undergoing primary surgery were identified. 88% of these patients had no evidence of disease at the conclusion of the study (average follow-up 45 months). Twenty were identified that had true positive IIM and 16 had very close IIM, with the remainder demonstrating widely negative margins. Tumor very close to or involving the deep margin but not a mucosal margin was associated with a higher risk of recurrence. Perineural invasion and lymphovascular invasion were associated with positive IIM. Positive or very close IIM on the deep margin was found to impact DSS and recurrence. CONCLUSION Obtaining negative IIM while performing TORS for HPV+ OPSCC is a modifiable factor that affects recurrence and DSS. Larger surgical margins should be considered in patients with perineural invasion or whose tumor abuts the initial deep margin. LEVEL OF EVIDENCE 4 Laryngoscope, 133:1132-1137, 2023.
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Affiliation(s)
- Alexandra Kejner
- Department of Otolaryngology - Head and Neck Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, U.S.A
| | - Christopher Gentile
- Department of Otorhinolaryngology, The University of Alabama School of Medicine, Birmingham, Alabama, U.S.A
| | - Zachary Porterfield
- Department of Otolaryngology - Head and Neck Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, U.S.A
- Department of Otorhinolaryngology, University of KwaZulu-Natal, Durban, South Africa
| | - William R Carroll
- Department of Otorhinolaryngology, The University of Alabama School of Medicine, Birmingham, Alabama, U.S.A
| | - Erin Partington Buczek
- Department of Otorhinolaryngology, The University of Alabama School of Medicine, Birmingham, Alabama, U.S.A
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Bedard MC, Chihanga T, Carlile A, Jackson R, Brusadelli MG, Lee D, VonHandorf A, Rochman M, Dexheimer PJ, Chalmers J, Nuovo G, Lehn M, Williams DEJ, Kulkarni A, Carey M, Jackson A, Billingsley C, Tang A, Zender C, Patil Y, Wise-Draper TM, Herzog TJ, Ferris RL, Kendler A, Aronow BJ, Kofron M, Rothenberg ME, Weirauch MT, Van Doorslaer K, Wikenheiser-Brokamp KA, Lambert PF, Adam M, Steven Potter S, Wells SI. Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer. Nat Commun 2023; 14:1975. [PMID: 37031202 PMCID: PMC10082832 DOI: 10.1038/s41467-023-37377-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 03/15/2023] [Indexed: 04/10/2023] Open
Abstract
Persistent HPV16 infection is a major cause of the global cancer burden. The viral life cycle is dependent on the differentiation program of stratified squamous epithelium, but the landscape of keratinocyte subpopulations which support distinct phases of the viral life cycle has yet to be elucidated. Here, single cell RNA sequencing of HPV16 infected compared to uninfected organoids identifies twelve distinct keratinocyte populations, with a subset mapped to reconstruct their respective 3D geography in stratified squamous epithelium. Instead of conventional terminally differentiated cells, an HPV-reprogrammed keratinocyte subpopulation (HIDDEN cells) forms the surface compartment and requires overexpression of the ELF3/ESE-1 transcription factor. HIDDEN cells are detected throughout stages of human carcinogenesis including primary human cervical intraepithelial neoplasias and HPV positive head and neck cancers, and a possible role in promoting viral carcinogenesis is supported by TCGA analyses. Single cell transcriptome information on HPV-infected versus uninfected epithelium will enable broader studies of the role of individual keratinocyte subpopulations in tumor virus infection and cancer evolution.
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Affiliation(s)
- Mary C Bedard
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Tafadzwa Chihanga
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Adrean Carlile
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Robert Jackson
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, 85721, USA
| | | | - Denis Lee
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
| | - Andrew VonHandorf
- Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Mark Rochman
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Phillip J Dexheimer
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Jeffrey Chalmers
- William G. Lowrie Department of Chemical and Biomolecular Engineering, Ohio State University, 151 W. Woodruff Ave, Columbus, OH, 43210, USA
| | - Gerard Nuovo
- Department of Pathology, Ohio State University Medical Center, Columbus, OH, 43210, USA
| | - Maria Lehn
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - David E J Williams
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, 85721, USA
- Medical Scientist Training M.D.-Ph.D. Program (MSTP), College of Medicine-Tucson, University of Arizona, Tucson, AZ, USA
| | - Aditi Kulkarni
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15232, USA
| | - Molly Carey
- Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA
| | - Amanda Jackson
- Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA
| | - Caroline Billingsley
- Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA
| | - Alice Tang
- Department of Otolaryngology, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Chad Zender
- Department of Otolaryngology, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Yash Patil
- Department of Otolaryngology, University of Cincinnati, Cincinnati, OH, 45267, USA
| | - Trisha M Wise-Draper
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Thomas J Herzog
- Department of Obstetrics and Gynecology, University of Cincinnati Medical Center, Cincinnati, OH, 45267, USA
| | - Robert L Ferris
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
- Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, 15232, USA
- Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15232, USA
| | - Ady Kendler
- Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Bruce J Aronow
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Matthew Kofron
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Marc E Rothenberg
- Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Matthew T Weirauch
- Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
- Divisions of Human Genetics, Biomedical Informatics and Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Koenraad Van Doorslaer
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, 85721, USA
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, 85721, USA
- The BIO5 Institute, University of Arizona, Tucson, AZ, 85721, USA
- Department of Immunobiology, University of Arizona, Tucson, AZ, 85721, USA
- UA Cancer Center, University of Arizona, Tucson, AZ, 85721, USA
| | - Kathryn A Wikenheiser-Brokamp
- Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
- Division of Pathology & Laboratory Medicine and The Perinatal Institute Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA
| | - Paul F Lambert
- McArdle Laboratory for Cancer Research, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53705, USA
| | - Mike Adam
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
| | - S Steven Potter
- Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
| | - Susanne I Wells
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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6
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Galati L, Chiocca S, Duca D, Tagliabue M, Simoens C, Gheit T, Arbyn M, Tommasino M. HPV and head and neck cancers: Towards early diagnosis and prevention. Tumour Virus Res 2022; 14:200245. [PMID: 35973657 PMCID: PMC9420391 DOI: 10.1016/j.tvr.2022.200245] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/29/2022] [Accepted: 08/08/2022] [Indexed: 01/13/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with an increasing trend of its incidence. Alcohol consumption, smoking, and viral infections, such as the mucosal high-risk (HR) human papillomaviruses (HPVs) are major risk factors for HNSCC development. In particular, HR HPVs are mainly associated with a subset of oropharyngeal squamous cell carcinoma (OPSCC), while other head and neck sites are marginally affected by HPV infection. HPV16 is the most frequently HR HPV type associated with HNSCC. In contrast to the cervix, no screening programs or identifiable pre-malignant lesions have been characterized for HPV-related HNSCC. Therefore, identification of general diagnostic algorithms and HPV biomarkers that could facilitate the early diagnosis, disease evolution and recurrence for HPV-driven HNSCCs are urgently needed. We herein review the role of HPV in HNSCC with a focus on epidemiology, biology, applied diagnostic algorithms and available biomarkers in body fluids as early diagnostic tools in HPV-driven HNSCCs.
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Affiliation(s)
- Luisa Galati
- International Agency for Research on Cancer, F-69372, Lyon, France
| | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Daria Duca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20139, Milan, Italy
| | - Marta Tagliabue
- Department of Otolaryngology and Head and Neck Surgery, IEO, European Institute of Oncology IRCCS, 20141, Milan, Italy; Department of Biomedical Sciences, University of Sassari, Sassari, Italy
| | - Cindy Simoens
- Unit of Cancer Epidemiology/Belgian Cancer Centre, Sciensano, 1050, Brussels, Belgium
| | - Tarik Gheit
- International Agency for Research on Cancer, F-69372, Lyon, France.
| | - Marc Arbyn
- Unit of Cancer Epidemiology/Belgian Cancer Centre, Sciensano, 1050, Brussels, Belgium; Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, University Ghent, Ghent, Belgium
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7
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Ai D, Dou Y, Ma C, Nan Z, Wang K, Dong Z, Tan W, Sun J, Qu X. Peri-tumoral infiltrate associates with postoperative prognosis of patients with OSCC: Stronger association in HPV negative patients. Am J Otolaryngol 2022; 43:103503. [PMID: 35636086 DOI: 10.1016/j.amjoto.2022.103503] [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: 01/07/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 11/01/2022]
Abstract
PURPOSE The current data on the relationship between local inflammatory infiltration and prognosis in oral squamous cell carcinoma (OSCC) are limited and controversial, especially in different HPV status. In this study, we analyzed the relationship between peri-tumoral inflammatory infiltrate (PTI) and HPV status and prognosis of patients with OSCC after surgery. METHODS A retrospective cohort of 99 primary OSCC patients who underwent surgery was constructed. P16 immunohistochemistry was used to determine HPV status. PTI was determined by hematoxylin-eosin staining and quantified into four levels: none (Score 0), weak (Score 1), moderate (Score 2) and strong (Score 3). The associations of PTI with clinico-pathological characteristics, HPV status and survival were examined. RESULTS Most OSCC patients had weak to moderate PTI. PTI was significantly associated with lymph node metastasis (P = 0.041), and patients with moderate PTI had significantly better OS (P = 0.009) than those with no PTI. In HPV negative OSCC, patients with moderate PTI also had significantly better OS (P = 0.019) than those with no PTI. However, PTI was not significantly associated with survival in HPV positive OSCC. CONCLUSIONS In HPV negative OSCC, moderate PTI may suggest a better postoperative prognosis than no PTI.
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8
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A Case of HPV-Associated Oropharyngeal Squamous Cell Carcinoma with Block-Like, Partial Loss of p16 Expression. Head Neck Pathol 2022; 16:1251-1256. [PMID: 35771403 PMCID: PMC9729667 DOI: 10.1007/s12105-022-01463-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 05/22/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Oropharyngeal squamous cell carcinoma is frequently associated with high-risk HPV infection, which confers a good prognosis. Immunohistochemistry for p16 is used as a surrogate for HPV status, but discrepant results are occasionally seen. Here, we report a case with a unique pattern of partial loss of p16. METHODS A 63 year old male presented with a base of tongue nonkeratinizing squamous cell carcinoma and a large metastatic neck mass. The primary lesion and multiple regions of the metastatic mass were assessed with p16 immunohistochemistry, RNA in situ hybridization for high-risk HPV, and HPV16 genome sequencing. RESULTS The primary lesion was p16 negative, and the metastatic neck mass had large, confluent regions that were either strongly p16 positive or entirely p16 negative. All of these regions were positive for high-risk HPV with identical HPV16 genomes. CONCLUSION This unusual case illustrates a potential diagnostic pitfall, and it raises important questions regarding molecular mechanisms and prognostic implications of p16 staining in oropharyngeal squamous cell carcinoma.
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9
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Internal heating method of loop-mediated isothermal amplification for detection of HPV-6 DNA. Mikrochim Acta 2022; 189:212. [PMID: 35507110 PMCID: PMC9065241 DOI: 10.1007/s00604-022-05283-9] [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: 01/17/2022] [Accepted: 03/14/2022] [Indexed: 11/02/2022]
Abstract
Loop-mediated isothermal amplification (LAMP) is a promising diagnostic tool for genetic amplification, which is known for its rapid process, simple operation, high amplification efficiency, and excellent sensitivity. However, most of the existing heating methods are external for completion of molecular amplification with possibility of contamination of specimens. The present research provided an internal heating method for LAMP using magnetic nanoparticles (MNPs), which is called nano-LAMP. Near-infrared light with an excitation wavelength of 808 nm was employed as the heating source; hydroxy naphthol blue (HNB) was used as an indicator to conduct methodological research. We demonstrate that the best temperature was controlled at a working power of 2 W and 4.8 µg/µL concentration of nanoparticles. The lowest limit for the detection of HPV by the nano-LAMP method is 102 copies/mL, which was confirmed by a gel electrophoresis assay. In the feasibility investigation of validated clinical samples, all 10 positive HPV-6 specimens amplified by nano-LAMP were consistent with conventional LAMP methods. Therefore, the nano-LAMP detection method using internal heating of MNPs may bring a new vision to the exploration of thermostatic detection in the future.
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10
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Head and Neck Squamous Cell Carcinoma: NT5E Could Be a Prognostic Biomarker. Appl Bionics Biomech 2022; 2022:3051907. [PMID: 35510041 PMCID: PMC9061055 DOI: 10.1155/2022/3051907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 04/08/2022] [Indexed: 11/24/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a type of tumour with a relatively poor prognosis. In recent years, immune checkpoint inhibitors, such as CTLA-4 and PD-1/PDL-1 inhibitors, have improved the treatment status of advanced tumours. However, the emergence of drug resistance has brought difficulties to clinical treatment, and new immune checkpoint research is imminent. The hypoxia-adenosine pathway, in which CD73 encoded by the NT5E gene is a key enzyme for adenosine production, has been identified as an immune checkpoint of great potential. Therefore, NT5E may play an important role in HNSCC. We performed a detailed bioinformatics analysis of NT5E in HNSCC, and the results showed that the overexpression of NT5E in HNSCC was associated with poor prognosis. Our further investigation of the coexpression pattern of HNSCC could provide a reference for drug resistance and immunotherapy studies.
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11
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Haddad RI, Seiwert TY, Chow LQM, Gupta S, Weiss J, Gluck I, Eder JP, Burtness B, Tahara M, Keam B, Kang H, Muro K, Albright A, Mogg R, Ayers M, Huang L, Lunceford J, Cristescu R, Cheng J, Mehra R. Influence of tumor mutational burden, inflammatory gene expression profile, and PD-L1 expression on response to pembrolizumab in head and neck squamous cell carcinoma. J Immunother Cancer 2022; 10:jitc-2021-003026. [PMID: 35217573 PMCID: PMC8883256 DOI: 10.1136/jitc-2021-003026] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2022] [Indexed: 12/13/2022] Open
Abstract
Background To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study. Methods Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106). Results TMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=–0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods. Conclusions TMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed. Trial registration number NCT01848834.
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Affiliation(s)
- Robert I Haddad
- Department of Medical Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
| | - Tanguy Y Seiwert
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois, USA
| | - Laura Q M Chow
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Shilpa Gupta
- Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Jared Weiss
- Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, North Carolina, USA
| | - Iris Gluck
- Department of Oncology, Sheba Medical Center at Tel HaShomer, Ramat Gan, Israel
| | - Joseph P Eder
- Department of Medicine, Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Barbara Burtness
- Division of Medical Oncology, Department of Internal Medicine, Yale School of Medicine and Yale Cancer Center, New Haven, Connecticut, USA
| | - Makoto Tahara
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hyunseok Kang
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland, USA
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | | | - Robin Mogg
- Merck & Co., Inc, Kenilworth, New Jersey, USA
| | - Mark Ayers
- Merck & Co., Inc, Kenilworth, New Jersey, USA
| | | | | | | | | | - Ranee Mehra
- Department of Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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12
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A New Look into Cancer-A Review on the Contribution of Vibrational Spectroscopy on Early Diagnosis and Surgery Guidance. Cancers (Basel) 2021; 13:cancers13215336. [PMID: 34771500 PMCID: PMC8582426 DOI: 10.3390/cancers13215336] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Cancer is a leading cause of death worldwide, with the detection of the disease in its early stages, as well as a correct assessment of the tumour margins, being paramount for a successful recovery. While breast cancer is one of most common types of cancer, head and neck cancer is one of the types of cancer with a lower prognosis and poor aesthetic results. Vibrational spectroscopy detects molecular vibrations, being sensitive to different sample compositions, even when the difference was slight. The use of spectroscopy in biomedicine has been extensively explored, since it allows a broader assessment of the biochemical fingerprint of several diseases. This literature review covers the most recent advances in breast and head and neck cancer early diagnosis and intraoperative margin assessment, through Raman and Fourier transform infrared spectroscopies. The rising field of spectral histopathology was also approached. The authors aimed at expounding in a more concise and simple way the challenges faced by clinicians and how vibrational spectroscopy has evolved to respond to those needs for the two types of cancer with the highest potential for improvement regarding an early diagnosis, surgical margin assessment and histopathology. Abstract In 2020, approximately 10 million people died of cancer, rendering this disease the second leading cause of death worldwide. Detecting cancer in its early stages is paramount for patients’ prognosis and survival. Hence, the scientific and medical communities are engaged in improving both therapeutic strategies and diagnostic methodologies, beyond prevention. Optical vibrational spectroscopy has been shown to be an ideal diagnostic method for early cancer diagnosis and surgical margins assessment, as a complement to histopathological analysis. Being highly sensitive, non-invasive and capable of real-time molecular imaging, Raman and Fourier transform infrared (FTIR) spectroscopies give information on the biochemical profile of the tissue under analysis, detecting the metabolic differences between healthy and cancerous portions of the same sample. This constitutes tremendous progress in the field, since the cancer-prompted morphological alterations often occur after the biochemical imbalances in the oncogenic process. Therefore, the early cancer-associated metabolic changes are unnoticed by the histopathologist. Additionally, Raman and FTIR spectroscopies significantly reduce the subjectivity linked to cancer diagnosis. This review focuses on breast and head and neck cancers, their clinical needs and the progress made to date using vibrational spectroscopy as a diagnostic technique prior to surgical intervention and intraoperative margin assessment.
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13
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Ai D, Dou Y, Nan Z, Wang K, Wang H, Zhang L, Dong Z, Sun J, Ma C, Tan W, Gao W, Liu J, Zhao L, Liu S, Song B, Shao Q, Qu X. CD68 + Macrophage Infiltration Associates With Poor Outcome of HPV Negative Oral Squamous Carcinoma Patients Receiving Radiation: Poly(I:C) Enhances Radiosensitivity of CAL-27 Cells but Promotes Macrophage Recruitment Through HMGB1. Front Oncol 2021; 11:740622. [PMID: 34568076 PMCID: PMC8459684 DOI: 10.3389/fonc.2021.740622] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/12/2021] [Indexed: 12/24/2022] Open
Abstract
Patients with human papillomavirus (HPV) negative oral squamous cell carcinoma (OSCC) generally have poor clinical outcomes and worse responses to radiotherapy. It is urgent to explore the underlining mechanisms of the distinct prognoses between HPV negative and HPV positive OSCC and to develop effective therapy strategy to increase the survival rate of HPV negative OSCC patients. We conducted a retrospective cohort of 99 resected OSCC patients to evaluate the prognosis of HPV negative and HPV positive OSCC patients receiving radiation or not. We further addressed the association of CD68+ macrophage infiltration with HPV status and the effects on survival of OSCC patients. We also used the TCGA-OSCC cohort for further verification. Based on the cohort study, we applied a synthetic dsRNA polymer, polyriboinosinic-polyribocytidylic acid (poly(I:C)), on CAL-27 (HPV negative OSCC cells). We co-cultured its condition medium with THP-1 derived macrophage and examined the cytokines and macrophage migration. We found that high CD68+ macrophage infiltration associated with poor overall survival in HPV negative OSCC patients receiving radiation. In vitro, poly(I:C) could induce apoptosis and enhance the radiosensitivity, but increase macrophage recruitment. Targeting HMGB1 could inhibit IL-6 induction and macrophage recruitment. Our findings indicated that CD68+ macrophage might play an important role in the outcomes of HPV negative OSCC patients receiving radiation. Our findings also suggested that radiation combined poly(I:C) might be a potential therapy strategy to increase the radiation response and prognosis of HPV negative OSCC. Notably, HMGB1 should be targeted to inhibit macrophage recruitment and enhance overall therapy effects.
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Affiliation(s)
- Dan Ai
- Laboratory of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Yu Dou
- School and Hospital of Stomatology, Cheelo College of Medicine, Shandong University, Jinan, China
| | - Zhaodi Nan
- Laboratory of Basic Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Ketao Wang
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University & Institute of Stomatology, Shandong University, Jinan, China
| | - Huayang Wang
- Department of Clinical Laboratory Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Lin Zhang
- Department of Clinical Laboratory Medicine, Qilu Hospital of Shandong University, Jinan, China
| | - Zuoqing Dong
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University & Institute of Stomatology, Shandong University, Jinan, China
| | - Jintang Sun
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Chao Ma
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Wanye Tan
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University & Institute of Stomatology, Shandong University, Jinan, China
| | - Wenjuan Gao
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Jia Liu
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Lei Zhao
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Shaohua Liu
- Department of Oral and Maxillofacial Surgery, Qilu Hospital of Shandong University & Institute of Stomatology, Shandong University, Jinan, China
| | - Bingfeng Song
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Qianqian Shao
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Xun Qu
- Laboratory of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
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14
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Genomic Characterization and Therapeutic Targeting of HPV Undetected Cervical Carcinomas. Cancers (Basel) 2021; 13:cancers13184551. [PMID: 34572780 PMCID: PMC8467954 DOI: 10.3390/cancers13184551] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 09/02/2021] [Accepted: 09/03/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Persistent HPV infection is a known driver of cervical carcinogenesis, but the existence and biological relevance of HPV undetected (HPVU) cervical cancer has been debated. Here we report the results of detailed molecular classification of HPVU cervical cancer, and validate HPVU as a biomarker of poor outcomes. We identify that HPVU cervical cancer tumors harbor mutations affecting cell cycle progression, and in vitro experiments reveal HPVU, but not HPV+, cells are sensitive to palbociclib monotherapy. HPVU status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments and these patients may benefit from personalized treatment plans. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPVU cervical cancer patients. We also suggest that primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Abstract Cervical cancer tumors with undetectable HPV (HPVU) have been underappreciated in clinical decision making. In this study, two independent CC datasets were used to characterize the largest cohort of HPVU tumors to date (HPVU = 35, HPV+ = 430). Genomic and transcriptome tumor profiles and patient survival outcomes were compared between HPV+ and HPVU tumors. In vitro analyses were done to determine efficacy of the selective CDK4/6 inhibitor palbociclib on HPVU cancer cell lines. Patients with HPVU CC tumors had worse progression-free and overall survival outcomes compared to HPV+ patients. TP53, ARID1A, PTEN, ARID5B, CTNNB1, CTCF, and CCND1 were identified as significantly mutated genes (SMGs) enriched in HPVU tumors, with converging functional roles in cell cycle progression. In vitro HPVU, but not HPV+, cancer cell lines with wild type RB1 were sensitive to palbociclib monotherapy. These results indicate that HPVU status can be translated into the clinic as a predictive biomarker of poor patient response to standard of care treatments. We suggest primary cervix tumors be routinely tested for HPV prior to treatment to identify patients who will benefit from more aggressive precision-driven therapy. Our results identify palbociclib as a lead candidate as an alternative treatment strategy for HPVU CC patients.
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15
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Orlandi M, Mazzei M, Vascellari M, Melchiotti E, Zanardello C, Verin R, Albanese F, Necci F, Pazzini L, Lazzarini G, Abramo F. Localization and genotyping of canine papillomavirus in canine inverted papillomas. J Vet Diagn Invest 2021; 33:1069-1078. [PMID: 34338089 DOI: 10.1177/10406387211035799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Numerous canine papillomaviruses (CPVs) have been identified (CPV1-23). CPV1, 2, and 6 have been associated with inverted papillomas (IPs). We retrieved 19 IPs from 3 histopathology archives, and evaluated and scored koilocytes, inclusion bodies, giant keratohyalin granules, cytoplasmic pallor, ballooning degeneration, and parakeratosis. IHC targeting major capsid proteins of PV was performed, and CPV genotyping was achieved by PCR testing. Tissue localization of CPV DNA and RNA was studied by chromogenic and RNAscope in situ hybridization (DNA-CISH, RNA-ISH, respectively). IPs were localized to the limbs (50%), trunk (30%), and head (20%), mainly as single nodules (16 of 19). In 15 of 19 cases, immunopositivity was detected within the nuclei in corneal and subcorneal epidermal layers. PCR revealed CPV1 in 11 IPs and CPV2 DNA in 3 IPs. Overall, 14 of 17 cases were positive by both DNA-CISH and RNA-ISH, in accord with PCR results. A histologic score >5 was always obtained in cases in which the viral etiology was demonstrated by IHC, DNA-CISH, and RNA-ISH. IHC and molecular approaches were useful to ascertain the viral etiology of IPs. Although IHC is the first choice for diagnostic purposes, ISH testing allows identification of PV type and the infection phase. RNA-ISH seems a promising tool to deepen our understanding of the pathogenesis of different PV types in animal species.
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Affiliation(s)
| | - Maurizio Mazzei
- Department of Veterinary Sciences, University of Pisa, Italy
| | - Marta Vascellari
- Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Padova, Italy
| | - Erica Melchiotti
- Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Padova, Italy
| | - Claudia Zanardello
- Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro, Padova, Italy
| | - Ranieri Verin
- Department of Veterinary Pathology and Public Health, University of Liverpool, UK.,Department of Comparative Biomedicine and Food Science, University of Padova, Italy
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Shinn JR, Davis SJ, Lang-Kuhs KA, Rohde S, Wang X, Liu P, Dupont WD, Plummer WD, Thorstad WL, Chernock RD, Mehrad M, Lewis JS. Oropharyngeal Squamous Cell Carcinoma With Discordant p16 and HPV mRNA Results: Incidence and Characterization in a Large, Contemporary United States Cohort. Am J Surg Pathol 2021; 45:951-961. [PMID: 33739785 PMCID: PMC8192336 DOI: 10.1097/pas.0000000000001685] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Early studies estimate that 5% to 10% of oropharyngeal squamous cell carcinomas overexpress p16 but are unassociated with transcriptionally-active high-risk human papillomavirus (HPV). Patients with discordant HPV testing may experience clinical outcomes that differ from traditional expectations. To document the rate of p16 and HPV mRNA positivity, characterize patients with discordant testing, and identify features that may warrant selective use of HPV-specific testing after p16 IHC, a multi-institutional, retrospective review of oropharyngeal squamous cell carcinoma patients with p16 IHC and HPV mRNA testing by reverse transcriptase polymerase chain reaction was performed. Of the 467 patients, most had T1 or T2 tumors (71%), 82% were p16 positive, and 84% were HPV mRNA positive. Overall, most tumors were nonkeratinizing (378, 81%), which was strongly associated with p16 and HPV positivity (93% and 95%, respectively). Overall, 81% of patients were double positive, 14% double negative, and 4.9% discordant (3.4% p16 negative/HPV mRNA positive and 1.5% p16 positive/HPV mRNA negative). The survival rates of these discordant patient groups fell squarely between the 2 concordant groups, although in multivariate analysis for both disease-free survival and overall survival, discordant patients were not found to have statistically significantly different outcomes. Reclassifying patients by applying HPV mRNA testing when p16 results and morphology do not match, or when p16 results are equivocal, improved prognostication slightly over p16 or HPV mRNA testing alone. Patients with discordant testing demonstrate a borderline significant trend toward survival differences from those with concordant tests. When evaluated independently, patients who were p16 negative but HPV mRNA positive had a prognosis somewhat closer to double-positive patients, while those who were p16 positive, but HPV mRNA negative had a prognosis closer to that of double-negative patients. We suggest an algorithm whereby confirmatory HPV mRNA testing is performed in patients where p16 status is not consistent with tumor morphology. This captures a majority of discordant patients and improves, albeit modestly, the prognostication.
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Affiliation(s)
- Justin R. Shinn
- Department of Otorhinolaryngology–Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA
| | - Seth J. Davis
- Department of Otolaryngology–Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Krystle A. Lang-Kuhs
- Department of Otolaryngology–Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN
- Department of Epidemiology, College of Public Health, University of Kentucky, Lexington, KY
| | - Sarah Rohde
- Department of Otolaryngology–Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Xiaowei Wang
- Department of Pharmacology and Regenerative Medicine, The University of Illinois at Chicago, IL
| | - Ping Liu
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - William D Dupont
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - W. Dale Plummer
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Wade L. Thorstad
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO
| | - Rebecca D. Chernock
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO
| | - Mitra Mehrad
- Department of Otolaryngology–Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
| | - James S. Lewis
- Department of Otolaryngology–Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
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Tokuzen N, Nakashiro KI, Tojo S, Goda H, Kuribayashi N, Uchida D. Human papillomavirus-16 infection and p16 expression in oral squamous cell carcinoma. Oncol Lett 2021; 22:528. [PMID: 34055093 PMCID: PMC8138897 DOI: 10.3892/ol.2021.12789] [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: 11/27/2020] [Accepted: 04/13/2021] [Indexed: 11/30/2022] Open
Abstract
Human papillomavirus (HPV) is a possible carcinogenetic factor in oral squamous cell carcinoma (OSCC). Previous studies have reported the prevalence of HPV in patients with OSCC. However, the association between HPV and OSCC remains controversial. The present study aimed to clarify the association between HPV infection, p16 protein expression and the clinicopathological characteristics of OSCC. The expression level of HPV-16E6 mRNA and p16 protein, a known surrogate marker of HPV infection, was investigated in 100 OSCC cases using TaqMan reverse transcription-quantitative PCR and immunohistochemistry staining, respectively. HPV-16E6 mRNA expression level was only detected in one case (1%), and positive expression of p16 was found in 10 cases (10%), including an HPV-positive case. Subsequently, the association between p16 expression level and clinicopathological characteristic factors were analyzed; however, no significant association was found. These results suggested that HPV-16 infection was less likely to cause OSCC in Japan and p16 expression was not a suitable marker for HPV infection in OSCC.
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Affiliation(s)
- Norihiko Tokuzen
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Koh-Ichi Nakashiro
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Shin Tojo
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Hiroyuki Goda
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Nobuyuki Kuribayashi
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
| | - Daisuke Uchida
- Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan
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18
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Jiromaru R, Yamamoto H, Yasumatsu R, Hongo T, Nozaki Y, Nakano T, Hashimoto K, Nakagawa T, Oda Y. p16 overexpression and Rb loss correlate with high-risk HPV infection in oropharyngeal squamous cell carcinoma. Histopathology 2021; 79:358-369. [PMID: 33450095 DOI: 10.1111/his.14337] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 01/04/2021] [Accepted: 01/12/2021] [Indexed: 11/27/2022]
Abstract
AIMS p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC), but it is not sufficient in all clinical settings. METHODS AND RESULTS We examined the p16 and Rb expression status in 177 OPSCC cases by immunohistochemistry and the presence of transcriptionally active HR-HPV infection by mRNA in-situ hybridisation. The 177 cases were divided into p16+ /HPV+ (n = 105, 59.3%), p16+ /HPV- (n = 8, 4.5%) and p16- /HPV- (n = 64, 36.2%) groups. The p16+ /HPV- and p16- /HPV- groups had a trend towards worse overall survival (OS) or significantly worse OS than the p16+ /HPV+ group (n = 105) (P = 0.0610, P = 0.0004, respectively). We divided the Rb status into preserved expression (> 90%, n = 68), partial loss (PL) (10-90%, n = 97) and complete loss (CL) (< 10%, n = 12). Among the HPV-positive cases (n = 105), the Rb pattern was typically PL (n = 97, 92.4%) and rarely CL (n = 8, 7.6%), but never preserved expression (0%). In contrast, among the HPV-negative cases (n = 72), the Rb pattern was typically preserved expression (n = 68, 94.4%) and rarely CL (n = 4, 5.6%), but never PL (0%). Compared to p16 alone, the combination of p16 overexpression and Rb-PL/CL showed equally excellent sensitivity (each 100%) and improved specificity (97.2 versus 88.9%) and positive predictive values (98.1 versus 92.9%). CONCLUSIONS These results suggest that the combined use of p16 and Rb immunohistochemistry could be a reliable, cost-effective method to predict HR-HPV infection in OPSCCs; however, HPV specific testing is necessary on inconclusive cases. We propose a diagnostic algorithm for practical use of these markers.
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Affiliation(s)
- Rina Jiromaru
- Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.,Department of Otorhinolaryngology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Ryuji Yasumatsu
- Department of Otorhinolaryngology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takahiro Hongo
- Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yui Nozaki
- Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takafumi Nakano
- Department of Otorhinolaryngology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kazuki Hashimoto
- Department of Otorhinolaryngology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takashi Nakagawa
- Department of Otorhinolaryngology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan
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19
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Frankart AJ, Criss BE, Dillehay McKillip K, Wise-Draper T, Takiar V, Kharofa J. Assessing the Reliability and Positive Predictive Value of p16 as a Surrogate for Human Papillomavirus-Mediated E6/7 mRNA Expression in Squamous Cell Carcinoma of the Anal Canal. Dis Colon Rectum 2021; 64:459-465. [PMID: 33394778 DOI: 10.1097/dcr.0000000000001836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Human papillomavirus has been implicated in the carcinogenesis of squamous cell carcinoma of the anal canal. p16 expression and the presence of human papillomavirus DNA have been used to define human papillomavirus-positive patients, but neither approach has been validated against the standard of human papillomavirus E6/7 mRNA expression at this disease site. OBJECTIVE This study aimed to evaluate the acceptability of p16 immunohistochemistry as a surrogate to E6/7 mRNA expression in identifying human papillomavirus-mediated squamous cell carcinoma of the anal canal. DESIGN This was a retrospective analysis of a previously constructed tissue microarray. SETTINGS This study was conducted at a tertiary academic center. PATIENTS Biopsies and resection specimens from patients diagnosed with squamous cell carcinoma of the anal canal at the study institution from 2005 to 2015 were reviewed for sample adequacy. MAIN OUTCOME MEASURES Concordance between p16 positivity by immunohistochemistry and E6/7 mRNA expression by in situ hybridization was evaluated. Sensitivity, specificity, and positive predictive value were assessed. RESULTS Among the 25 patients evaluated, p16 and E6/7 mRNA results were concordant in 24 of 25 specimens (96%). Of the 24 concordant samples, there were 23 true positives (p16+ and E6/7+) and 1 true negative (p16- and E6/7-). One specimen was discordant (p16- and E6/7+) between p16 and E6/7 mRNA (4%). This resulted in a sensitivity of 96% and a specificity of 100%. Positive predictive value of p16 immunohistochemistry for E6/7 mRNA expression was 100%. LIMITATIONS This study was limited by its retrospective nature and small sample size. It only assessed diagnostic parameters rather than prognostic implications. CONCLUSIONS In this study, the clinically prevalent method of p16 immunohistochemistry showed excellent concordance with the standard of E6/7 mRNA expression and demonstrated its potential to serve as a surrogate for identifying human papillomavirus-induced squamous cell carcinoma of the anal canal. See Video Abstract at http://links.lww.com/DCR/B448. EVALUANDO LA CONFIABILIDAD Y EL VALOR PREDICTIVO POSITIVO DE P, COMO SUSTITUTO DE LA EXPRESIN DE ARNM DE E / , MEDIADA POR EL VIRUS DEL PAPILOMA HUMANO, EN CARCINOMA DE CLULAS ESCAMOSAS DEL CANAL ANAL ANTECEDENTES:El virus del papiloma humano se ha relacionado en la carcinogénesis del carcinoma de células escamosas del canal anal. La expresión de p16 y la presencia de ADN del virus del papiloma humano, se han utilizado para definir a los pacientes positivos al virus del papiloma humano. Pero ninguno de estos enfoques, han sido validados frente al estándar de oro de la expresión del ARNm del virus del papiloma humano E6 / 7, en este sitio de la enfermedad.OBJETIVO:El estudio tuvo como objetivo, evaluar la aceptabilidad de la inmunohistoquímica del p16, como sustituto de la expresión de ARNm de E6 / 7, en la identificación del carcinoma de células escamosas del canal anal, mediada por virus del papiloma humano.DISEÑO:Fue un análisis retrospectivo de un microarreglo de tejido previamente construido.AJUSTE:El estudio se realizó en un centro académico terciario.PACIENTES:Se revisaron biopsias y muestras de resección de pacientes diagnosticados con carcinoma de células escamosas del canal anal, en la institución del estudio, entre 2005 y 2015 para determinar la idoneidad de la muestra.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluó la concordancia entre la positividad de p16 por inmunohistoquímica y la expresión de ARNm de E6 / 7 por hibridación in situ. Se evaluaron la sensibilidad, especificidad y valor predictivo positivo.RESULTADOS:Entre los 25 pacientes evaluados, los resultados del ARNm de p16 y E6 / 7 fueron concordantes en 24/25 muestras (96%). De las 24 muestras concordantes, hubo 23 positivos verdaderos (p16 + y E6 / 7 +) y un negativo verdadero (p16- y E6 / 7-). Una muestra fue discordante (p16- y E6 / 7 +) entre p16 y ARNm de E6 / 7 (4%). Esto resultó en una sensibilidad del 96% y una especificidad del 100%. El valor predictivo positivo de la inmunohistoquímica de p16 para la expresión de ARNm de E6 / 7 fue del 100%.LIMITACIONES:El estudio estuvo limitado por su naturaleza retrospectiva y por el tamaño pequeño de la muestra. Solamente evaluó los parámetros de diagnóstico, en lugar de las implicaciones pronosticas.CONCLUSIONES:En este estudio, el método clínico prevalente de inmunohistoquímica p16, mostró una excelente concordancia con el estándar de oro de la expresión de ARNm de E6 / 7 y demostró su potencial para servir, como sustituto para identificar el carcinoma de células escamosas del canal anal, inducido por el virus del papiloma humano. Consulte Video Resumen en http://links.lww.com/DCR/B448.
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Affiliation(s)
- Andrew J Frankart
- Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Benjamin E Criss
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio
| | | | - Trisha Wise-Draper
- Division of Hematology Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Vinita Takiar
- Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio
| | - Jordan Kharofa
- Department of Radiation Oncology, University of Cincinnati, Cincinnati, Ohio
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20
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Suresh K, Shah PV, Coates S, Alexiev BA, Samant S. In situ hybridization for high risk HPV E6/E7 mRNA in oropharyngeal squamous cell carcinoma. Am J Otolaryngol 2021; 42:102782. [PMID: 33171410 DOI: 10.1016/j.amjoto.2020.102782] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 10/17/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVES To report a single institution's experience using human papillomavirus (HPV) E6/E7 mRNA in-situ hybridization (mRNA ISH) for HPV detection in oropharyngeal squamous cell carcinoma (OPSCC). To review the literature on HPV detection methods. STUDY DESIGN Retrospective chart review, literature review. SETTING Tertiary care academic hospital. SUBJECTS AND METHODS We conducted a retrospective chart review of 122 OPSCC biopsy specimens. mRNA ISH was performed on formalin-fixed paraffin-embedded (FFPE) tissue with a pool of 18 high risk HPV probes using an automated stainer; p16 immunohistochemistry (IHC) was also performed. We conducted a literature review on HPV detection methods including p16 IHC, mRNA ISH, DNA ISH, and PCR. RESULTS In our cohort, mRNA ISH had a sensitivity and specificity of 100% and 100% with reference to p16 (100% concordance). 2-year OS was 87.5% vs. 94.5% for p16/HPV-negative vs. positive patients. 2-year DFS was 60.0% vs. 84.2%. On literature review, mRNA ISH demonstrated consistently high sensitivity and specificity ranging from 88-98% and 90-100% respectively. In comparison, the specificity of p16 was 85-95%. CONCLUSIONS Our report supports the use of mRNA ISH for HPV detection in OPSCC and validates its feasibility using automated tissue staining methods on FFPE tissue. Our findings and literature review support that mRNA ISH may have superior specificity and be easier to interpret than p16. Further study on the prognostic value and cost-effectiveness of mRNA ISH is warranted and may establish this HPV detection method as the "gold standard."
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Affiliation(s)
- Krish Suresh
- Department of Otolaryngology - Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Parth V Shah
- Department of Otolaryngology - Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Sydney Coates
- Department of Otolaryngology - Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Borislav A Alexiev
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America
| | - Sandeep Samant
- Department of Otolaryngology - Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America.
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21
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Kawashita S, Matsuda K, Matsuwaki T, Kurohama H, Ito M, Kishikawa M, Miura K, Nakashima M. Cervical Superficially Invasive Squamous Cell Carcinoma With Supraclavicular Lymph Node Metastasis: A Case Report. Int J Gynecol Pathol 2021; 40:78-83. [PMID: 32897965 DOI: 10.1097/pgp.0000000000000679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Typically, local spread and lymph-vascular space invasion (LVSI) occur before lymph node (LN) and distant metastases during the progression of uterine cervical cancer. The prognostic value of LVSI in cervical superficially invasive squamous cell carcinoma (SISCC) is still debated. We encountered a rare case of cervical SISCC without LVSI presenting with multiple LN metastases, including pelvic, para-aortic, and left supraclavicular LNs. Immunohistochemical analysis of p16 and in situ hybridization of human papillomavirus confirmed the relationship of the cervical SISCC and pelvic LN metastases. Aspiration cytology of the left supraclavicular LN showed squamous cell carcinoma and our final diagnosis was uterine cervical squamous cell carcinoma, stage IVB. The patient underwent adjuvant chemotherapy. Although relapse was observed at the vaginal stump and in pelvic and para-aortic LNs, chemotherapy and radiotherapy were effective. The patient is alive without disease 40 mo after initial treatment. This is the first case report of cervical SISCC without LVSI presenting with supraclavicular LN metastasis, which contributes to our understanding of the value of LVSI. Immunohistochemical analysis of p16 and in situ hybridization of human papillomavirus were useful in confirming the relationship of cervical SISCC and its metastases. As cervical SISCC with LN metastasis is rare, multi-institutional joint research is needed to clarify its prognosis and appropriate treatment.
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22
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Dwedar RA, Omar NM, Eissa SAL, Badawy AYA, El-Kareem DA, Ahmed Madkour LAEF. Diagnostic and prognostic impact of E6/E7 mRNA compared to HPV DNA and p16 expression in head and neck cancers: an Egyptian study. ALEXANDRIA JOURNAL OF MEDICINE 2020. [DOI: 10.1080/20905068.2020.1827944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Affiliation(s)
- Reham Ali Dwedar
- Department of Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Noha Mohamed Omar
- Department of Microbiology and Immunology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | | | - Dalia Abd El-Kareem
- Department of Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
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23
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Augustin JG, Lepine C, Morini A, Brunet A, Veyer D, Brochard C, Mirghani H, Péré H, Badoual C. HPV Detection in Head and Neck Squamous Cell Carcinomas: What Is the Issue? Front Oncol 2020; 10:1751. [PMID: 33042820 PMCID: PMC7523032 DOI: 10.3389/fonc.2020.01751] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/05/2020] [Indexed: 12/15/2022] Open
Abstract
Besides classic tobacco and alcohol risk factors, human papillomavirus (HPV) plays a role in the development of a subset of head and neck squamous cell carcinomas (HNSCCs), and notably oropharynx squamous cell carcinomas (OPSCCs). HPV-induced OPSCCs have a different biological behavior and a better prognosis compared to non-HPV-induced OPSCCs and the eighth-edition TNM classification now separates these two entities. Therefore, determining the HPV status of patients with OPSCC is now essential for treatment, prognosis, and development of clinical trials. In this review, after reminding essential steps of HPV implication in the cell cycle, we describe the existing tools that are currently feasible in routine practice according to facilities available in health structures, with their benefits and drawbacks: HPV PCR, E6/E7 mRNA RT-PCR, E6/E7 mRNA in situ hybridization, HPV DNA in situ hybridization, and P16 immunochemistry. Besides these traditional HPV detection tools, novel diagnostic approaches are being evaluated for HPV-induced OPSCC “ultrastaging.” E6 humoral response and ddPCR-detecting HPVct DNA are two techniques performed on blood and are therefore non-invasive. Baseline E6 humoral levels could have a prognostic value, and HPVct DNA could be helpful for HPV OPSCC recurrence monitoring. At last, next-generation sequencing (NGS)-based “capture HPV” is a technique feasible on biopsies and circulating DNA material. It helps characterize HPV integration status and sites, and it could define prognostic subgroups in HPV-induced OPSCC. These novel precision detection tools could be further integrated in the care of patients with HPV-induced OPSCC.
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Affiliation(s)
| | - Charles Lepine
- Department of Pathology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France.,INSERM U970, Université de Paris, Paris, France.,Equipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Aurelien Morini
- Department of Pathology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France
| | - Anais Brunet
- Department of Pathology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France
| | - David Veyer
- Department of Virology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France
| | - Camille Brochard
- Department of Pathology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France
| | - Haitham Mirghani
- Department of Head and Neck Surgery, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France
| | - Hélène Péré
- INSERM U970, Université de Paris, Paris, France.,Equipe Labellisée Ligue Contre le Cancer, Paris, France.,Department of Virology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France
| | - Cécile Badoual
- Department of Pathology, European Georges Pompidou Hospital, APHP, Université de Paris, Paris, France.,INSERM U970, Université de Paris, Paris, France.,Equipe Labellisée Ligue Contre le Cancer, Paris, France
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24
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Cocks M, Chaux A, Jenson EG, Miller JA, Rodriguez Pena MDC, Tregnago AC, Taheri D, Eich ML, Sharma R, Vang R, Netto GJ. Immune checkpoint status and tumor microenvironment in vulvar squamous cell carcinoma. Virchows Arch 2020; 477:93-102. [PMID: 31993774 DOI: 10.1007/s00428-020-02759-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 12/31/2019] [Accepted: 01/21/2020] [Indexed: 12/31/2022]
Abstract
Vulvar squamous cell carcinoma accounts for 5% of cancers of the female genital tract. Current guidelines recommend wide local excision with negative surgical margins as the standard treatment. However, the extent of the tumor-free resection margin after wide local excision is still controversial in many cases. Drugs targeting immune checkpoints such as PD-1 or its ligand PD-L1 have potential clinical utility in these patients. We examined the expression of PD-L1 in tumor cells and immune cells, as well as the proportion of PD-1, CD8, and FOXP3 positive lymphocytes. Twenty-one cases of invasive vulvar squamous cell carcinomas were reviewed. Whole slides of representative formalin-fixed, paraffin-embedded archival material were used for analysis. Odds ratios (OR) and hazard ratios (HR) were used to estimate risk for disease recurrence, overall mortality, and cancer mortality. PD-L1 expression was found in 43% of tumor cells, with higher proportions in intratumoral (67%) and peritumoral (81%) immune cells. OR and HR for disease recurrence and cancer mortality were higher in tumors with higher CD8 expression. OR and HR for overall mortality were also higher in tumors with higher PD-L1 and CD8 expression. In conclusion, nearly half of cases were PD-L1 positive in tumor cells with over two-third of cases demonstrating PD-L1 positivity in immune cells. Immunohistochemical expression of PD-L1 and CD8 could be used to suggest higher risk of disease recurrence, overall mortality, and cancer mortality. Furthermore, our data contributes to the growing evidence that targeting the PD-1/PD-L1 pathway may be beneficial in vulvar squamous cell carcinomas.
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Affiliation(s)
- Margaret Cocks
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
| | - Alcides Chaux
- Department of Scientific Research, School of Postgraduate Studies, Norte University, Asunción, Paraguay
| | - Erik G Jenson
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
| | - James A Miller
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
| | - Maria Del Carmen Rodriguez Pena
- Department of Pathology, The University of Alabama at Birmingham, West Pavilion P210, 619 19th Street, South Birmingham, AL, 35249-7331, USA
| | - Aline C Tregnago
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
| | - Diana Taheri
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
- Isfahan Kidney Diseases Research Center, Pathology, Isfahan University of Medical Sciences, Isfahan, Islamic Republic of Iran
| | - Marie-Lisa Eich
- Department of Pathology, The University of Alabama at Birmingham, West Pavilion P210, 619 19th Street, South Birmingham, AL, 35249-7331, USA
- Department of Pathology, University Hospital Cologne, Cologne, Germany
| | - Rajni Sharma
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
| | - Russell Vang
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA
| | - George J Netto
- Department of Pathology, The University of Alabama at Birmingham, West Pavilion P210, 619 19th Street, South Birmingham, AL, 35249-7331, USA.
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25
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Sharma P, Gautam SD, Rajendra S. Importance of investigating high-risk human papillomavirus in lymph node metastasis of esophageal adenocarcinoma. World J Gastroenterol 2020; 26:2729-2739. [PMID: 32550750 PMCID: PMC7284187 DOI: 10.3748/wjg.v26.i21.2729] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/18/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023] Open
Abstract
High-risk human papillomavirus has been suggested as a risk factor for esophageal adenocarcinoma. Tumor human papillomavirus status has been reported to confer a favorable prognosis in esophageal adenocarcinoma. The size of the primary tumor and degree of lymphatic spread determines the prognosis of esophageal carcinomas. Lymph node status has been found to be a predictor of recurrent disease as well as 5-year survival in esophageal malignancies. In human papillomavirus driven cancers, e.g. cervical, anogenital, head and neck cancers, associated lymph nodes with a high viral load suggest metastatic lymph node involvement. Thus, human papillomavirus could potentially be useful as a marker of micro-metastases. To date, there have been no reported studies regarding human papillomavirus involvement in lymph nodes of metastatic esophageal adenocarcinoma. This review highlights the importance of investigating human papillomavirus in lymph node metastasis of esophageal adenocarcinoma based on data derived from other human papillomavirus driven cancers.
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Affiliation(s)
- Preeti Sharma
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales 2170, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
| | - Shweta Dutta Gautam
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales 2170, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
| | - Shanmugarajah Rajendra
- Gastro-Intestinal Viral Oncology Group, Ingham Institute for Applied Medical Research, Liverpool, Sydney, New South Wales 2170, Australia
- South Western Sydney Clinical School, University of New South Wales, Kensington, Sydney, New South Wales 2052, Australia
- Department of Gastroenterology & Hepatology, Bankstown-Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown, Sydney, New South Wales 2200, Australia
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26
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Patel JJ, Levy DA, Nguyen SA, Knochelmann HM, Day TA. Impact of PD-L1 expression and human papillomavirus status in anti-PD1/PDL1 immunotherapy for head and neck squamous cell carcinoma-Systematic review and meta-analysis. Head Neck 2020; 42:774-786. [PMID: 31762164 PMCID: PMC7147243 DOI: 10.1002/hed.26036] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/30/2019] [Accepted: 11/13/2019] [Indexed: 12/24/2022] Open
Abstract
Programmed cell death-1 (PD-1) pathway inhibition in head and neck squamous cell carcinoma (HNSCC) has demonstrated inconsistent efficacy regarding human papillomavirus (HPV) status and PD-L1 expression. This study compared outcomes in HNSCC in the context of PD-L1 and HPV expression. Outcomes: PD-L1 and HPV expression; overall survival (OS), and tumor response (ORR). 1088 patients received PD-1/L1 inhibitors. Four methodologies were identified in determining PD-L1 expression, most commonly using the Dako PD-L1 IHC 22C3 pharmaDx assay. Using a 1% threshold, ORR was greater for PD-L1 expressers vs non-expressers (18.9%, CI 16.1-21.8 v 8.8% CI 5.3-13.7, P = 0.009), as was OS at 6 months (60.6%, CI 49.2-71.4 v 49.0%, CI 39.1-59.0, P = 0.04) but not at 12 or 18 months. No advantages were identified for HPV expressers. Patients expressing PD-L1 may have a better tumor response and OS. No impact on survival or response was observed based on HPV status.
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Affiliation(s)
- Jaimin J. Patel
- Head and Neck Tumor Center, Hollings, Cancer Center Department of Otolaryngology—Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Dylan A. Levy
- Head and Neck Tumor Center, Hollings, Cancer Center Department of Otolaryngology—Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina
- Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, Connecticut
| | - Shaun A. Nguyen
- Head and Neck Tumor Center, Hollings, Cancer Center Department of Otolaryngology—Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Hannah M. Knochelmann
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Terry A. Day
- Head and Neck Tumor Center, Hollings, Cancer Center Department of Otolaryngology—Head and Neck Surgery, Medical University of South Carolina, Charleston, South Carolina
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27
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An HJ, Koh HM, Song DH. New P16 Expression Criteria Predict Lymph Node Metastasis in Patients With Non-small Cell Lung Cancer. In Vivo 2020; 33:1885-1892. [PMID: 31662516 DOI: 10.21873/invivo.11682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 07/14/2019] [Accepted: 07/30/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND There have been many attempts to predict the prognosis of lung cancer based on the expression patterns of P16 protein, but with limited success. The Eighth American Joint Committee on Cancer (AJCC) for head and neck cancer recently developed new criteria for evaluating P16 expression. Here, we applied these new criteria to evaluate the prognosis of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS A total of 148 patients who had undergone surgery for NSCLC were enrolled in the study. P16 protein expression patterns from NSCLC tissue microarray samples were examined by immunohistochemical analysis. The Eighth AJCC head and neck cancer staging criteria were used to evaluate positive P16 expression (moderate/strong nuclear expression intensity and distribution >75% cells) in NSCLC. The relationship between P16 expression and clinicopathological factors were evaluated and survival analysis was included. RESULTS Negative P16 expression was significantly associated with NSCLC with lymph node metastasis (p=0.025). In addition, patients with NSCLC with negative P16 expression demonstrated poor disease-free and disease-specific survival in multivariate analysis. The Kaplan-Meier survival curve confirmed that negative P16 expression was significantly correlated with a poor disease-free survival (p=0.017) and disease-specific survival (p=0.016). CONCLUSION P16 expression defined with the new AJCC criteria is useful for detecting lymph node metastasis in NSCLC.
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Affiliation(s)
- Hyo Jung An
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
| | - Hyun Min Koh
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
| | - Dae Hyun Song
- Department of Pathology, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea .,Gyeongsang National University School of Medicine, Jinju, Republic of Korea.,Gyeongsang Institute of Health Science, Jinju, Republic of Korea
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Augustin J, Outh-Gauer S, Mandavit M, Lépine C, Broudin C, Hans S, Péré H, Badoual C. [Study of the Human Papillomavirus (HPV) prevalence in head and neck carcinomas in a French monocentric cohort of 372 patients]. Ann Pathol 2020; 40:401-410. [PMID: 32081547 DOI: 10.1016/j.annpat.2020.01.005] [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: 11/25/2019] [Revised: 01/14/2020] [Accepted: 01/22/2020] [Indexed: 10/25/2022]
Abstract
INTRODUCTION French data about HPV role in head and neck carcinomas are sparse, although French patients are mostly heavy smokers. In this series of oropharyngeal et non-oropharyngeal tumors, we aimed to determine what were the clinicopathological features associated with HPV and evaluate survival of patients according to HPV status. METHODS Three hundred and seventy-two cases of head and neck squamous cell carcinomas were reviewed and clinicopathological data were detailed. For each case, we performed a HPV PCR and an immunostaining against p16 protein (paraffin embedded tissues). RESULTS The series contained 90% of heavy smokers and 36% of tumors were located in oropharynx. HPV DNA was detected in 46% of oropharyngeal carcinomas and 16% of non-oropharyngeal carcinomas. Genotype 16 was the most frequently detected (84%). Clinicopathological features significantly associated with HPV DNA were: oropharyngeal location; absence of tobacco smoking; nodal involvement; poorly-differentiated non-keratinizing histology; positive p16 immunostaining. HPV infection was significantly associated with a longer survival for oropharyngeal carcinomas. It was not the case for non-oropharyngeal carcinomas. CONCLUSION In this French series with lot of heavy smokers, under half of carcinomas are HPV induced. Clinicopathological features and survival data associated with HPV infection are the same as those classically described in literature.
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Affiliation(s)
- Jérémy Augustin
- Service d'anatomie et cytologie pathologiques, hôpital européen Georges Pompidou, AP-HP, 75015 Paris, France; Faculté de médecine, Sorbonne universités, 75006 Paris, France.
| | - Sophie Outh-Gauer
- Service d'anatomie et cytologie pathologiques, hôpital européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Marion Mandavit
- Inserm U970, université Paris Descartes Sorbonne Paris, 75015 Paris, France; Équipe labellisée ligue contre le cancer, 75013 Paris, France
| | - Charles Lépine
- Service d'anatomie et cytologie pathologiques, hôpital européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Chloé Broudin
- Service d'anatomie et cytologie pathologiques, hôpital européen Georges Pompidou, AP-HP, 75015 Paris, France
| | - Stéphane Hans
- Service d'ORL, hôpital européen Georges-Pompidou, AP-HP, 75015 Paris, France
| | - Hélène Péré
- Service de virologie, hôpital européen Georges-Pompidou, AP-HP, 75015 Paris, France
| | - Cécile Badoual
- Service d'anatomie et cytologie pathologiques, hôpital européen Georges Pompidou, AP-HP, 75015 Paris, France; Inserm U970, université Paris Descartes Sorbonne Paris, 75015 Paris, France; Équipe labellisée ligue contre le cancer, 75013 Paris, France
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van Zante A, Jordan RC. Detection Methods for Human Papillomavirus (HPV) in Head and Neck Cancers. TEXTBOOK OF ORAL CANCER 2020. [DOI: 10.1007/978-3-030-32316-5_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Nopmaneepaisarn T, Tangjaturonrasme N, Rawangban W, Vinayanuwattikun C, Keelawat S, Bychkov A. Low prevalence of p16-positive HPV-related head-neck cancers in Thailand: tertiary referral center experience. BMC Cancer 2019; 19:1050. [PMID: 31694600 PMCID: PMC6836494 DOI: 10.1186/s12885-019-6266-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 10/15/2019] [Indexed: 11/15/2022] Open
Abstract
Background There has been a sharp rise in the incidence of human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) in many countries. Patients with HPV-positive OPSCC have a more favorable prognosis compared with HPV-negative OPSCC, leading to investigation and adoption of de-escalation treatment protocols. The baseline rate of HPV prevalence in certain populations is of epidemiologic significance. We aimed to evaluate the rate of high-risk HPV in a large cohort of Thai patients, including OPSCC, oral SCC (OSCC) and laryngeal SCC (LSCC). Methods In total, 504 patients with HN cancer (110 OPSCC, 260 OSCC and 134 LSCC) who had been treated in Chulalongkorn University between 2010 and 2016 formed the sample set. All histological slides were reviewed to validate the diagnosis and render the histological type as keratinizing (K), non-keratinizing (NK) or non-keratinizing with maturation (NK-M). Immunohistochemistry with p16 was performed in all cases and scored semiquantatively. Positive and equivocal cases were tested by the high-risk HPV DNA in situ hybridization (ISH). Validation with quantitative polymerase-chain reaction (qPCR) was performed in p16-positive OPSCC. Results The OPSCC were represented by NK (7.3%), NK-M (16.4%) and K (76.4%) types, with an HPV incidence of 100, 22.2 and 4.7%, respectively. The average HPV prevalence in OPSCC was 14.5%. The concordance with p16/ISH was 51.6%, while concordance of the NK morphology with positive HPV ISH was 100%. ISH-qPCR concordance in p16-positive OPSCC was 72.7%. Patients with HPV-positive OPSCC had significantly more tumors with a NK histologic type, tonsillar location, earlier clinical stage, less association with smoking, and, finally, better outcome and longer survival time. In non-OPSCC, p16-positive HPV-associated cancers were found in only 1.5% of OSCC (4/260) and LSCC (2/134). Conclusion A low rate of HPV-related OPSCC was found in Thai patients. The NK morphology was an excellent predictor of high-risk HPV infection in OPSCC. For OPSCC patients, HPV-positive ones had a significantly longer survival time than HPV-negative ones. There was a lack of p16-positive HPV-related OSCC and LSCC. Morphology and p16 status had a poor predictive value for detecting HPV in OSCC and LSCC.
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Affiliation(s)
- Titaporn Nopmaneepaisarn
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Napadon Tangjaturonrasme
- Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Rama IV Rd., Pathumwan, Bangkok, 10330, Thailand.
| | - Worawat Rawangban
- Department of Otolaryngology, Faculty of Medicine, Chulalongkorn University, Rama IV Rd., Pathumwan, Bangkok, 10330, Thailand
| | - Chanida Vinayanuwattikun
- Department of Internal Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.,The King Chulalongkorn Memorial Hospital, Bangkok, 10330, Thailand
| | - Somboon Keelawat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Andrey Bychkov
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.,Department of Pathology, Kameda Medical Center, Kamogawa, Chiba, 296-8602, Japan.,Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8523, Japan
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Sudhakaran A, Hallikeri K, Babu B. p16 as an independent marker for detection of high-risk HPV in oral submucous fibrosis and oral squamous cell carcinoma. INDIAN J PATHOL MICR 2019; 62:523-528. [PMID: 31611434 DOI: 10.4103/ijpm.ijpm_838_18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background An alarming increase in incidence of high-risk human papillomavirus (HPV) positive tumors in head and neck squamous cell carcinoma (HNSCC) by 25% and 70% in oropharyngeal HNSCC cannot be ignored. The early oncogenes of HPV, E6, and E7 play a key role in carcinogenesis. HPV associated tumors have a better clinical outcome and a favorable prognosis. The p16 expression has high concordance with other methods of HPV detection, ascertaining p16 as a surrogate marker for HPV. Objective To assess the immunohistochemical expression of p16 in oral submucous fibrosis (OSF) and oral squamous cell carcinoma (OSCC) with and without coexistent OSF as a marker for high-risk HPV detection. Materials and. Methods Tissue blocks of 70 cases including normal, OSF, OSCC with and without OSF were subjected to IHC staining with a p16INK4A monoclonal antibody. (Biogenex, San Roman). The p16 expression was noted according to percent positivity and pattern. The data were tabulated, statistically analyzed using the Chi-square test and the P value was assessed. Results The percentage of p16 positive cells raised from normal to OSF to OSCC with and without OSF. In addition, a shift from nuclear to cytoplasmic expression from normal to OSCC was noted with a statistical significance (P < 0.001). However, no statistical significance was established with any clinicopathologic parameters except age (P = 0.012) and habits (P= 0.023). Conclusion The presence of HPV using p16 was not detected in OSF but was positive in OSCC. Altered pattern of expression from normal to OSF to OSCC indicates promising use of p16 as a diagnostic marker.
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Affiliation(s)
- Archana Sudhakaran
- Department of Oral and Maxillofacial Pathology, SDM College of Dental Sciences and Hospital, Dharwad, Bangalore, Karnataka, India
| | - Kaveri Hallikeri
- Department of Oral and Maxillofacial Pathology, SDM College of Dental Sciences and Hospital, Dharwad, Bangalore, Karnataka, India
| | - Biji Babu
- Department of Oral and Maxillofacial Pathology, SDM College of Dental Sciences and Hospital, Dharwad, Bangalore, Karnataka, India
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Wong KS, Krane JF, Jo VY. Heterogeneity of p16 immunohistochemistry and increased sensitivity of RNA in situ hybridization in cytology specimens of HPV-related head and neck squamous cell carcinoma. Cancer Cytopathol 2019; 127:632-642. [PMID: 31509355 DOI: 10.1002/cncy.22178] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/29/2019] [Accepted: 07/31/2019] [Indexed: 11/11/2022]
Abstract
BACKGROUND Many patients with human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HPV-HNSCC) initially present with cervical lymph node metastases. Although p16 immunohistochemistry (IHC) is the most commonly used surrogate marker for HPV, however criteria in cytologic material are not well established. The objective of this study was to better characterize p16 IHC in cell blocks of metastatic HPV-HNSCC, and to evaluate the performance of HPV RNA in situ hybridization (RNA ISH). METHODS p16 IHC was performed on cell blocks from 97 metastatic HPV-HNSCC fine-needle aspiration specimens with HPV status confirmed by DNA or RNA ISH or polymerase chain reaction (PCR). Tumor cellularity (<100 cells, 100-500 cells, and >500 cells) and quality (presence of cell clusters, necrosis) were recorded. p16 staining intensity and extent (1%-9%, 10%-69%, and ≥70%) were scored. In addition, RNA ISH was performed on 38 PCR-positive cases. RESULTS p16 IHC was positive in 90 of 97 cases (93%), demonstrating variable patterns. p16 staining was found to be moderate to strong in 69 cases, with 37 cases (38%) demonstrating positivity in ≥70% of tumor cells. Weak staining occurred in 21 cases (22%) and 7 cases (7%) were negative. Of the 60 cases with weak and/or absent expression or staining in <70% of cells, 30 cases (50%) had <100 tumor cells, 12 (20%) lacked cell clusters, and 19 cases (32%) had extensive necrosis. RNA ISH was positive in 37 of 38 cases (97%) that were HPV positive by PCR. CONCLUSIONS p16 is heterogeneous in cell blocks of metastatic HPV-HNSCC, suggesting that any p16 positivity should prompt confirmatory HPV studies. RNA ISH appears to demonstrate high sensitivity, and laboratories even may consider using RNA ISH as a first-line HPV test in cytologic specimens.
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Affiliation(s)
- Kristine S Wong
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Jeffrey F Krane
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California
| | - Vickie Y Jo
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts
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Keung ES, Souers RJ, Bridge JA, Faquin WC, Graham RP, Hameed MR, Lewis JS, Merker JD, Vasalos P, Moncur JT. Comparative Performance of High-Risk Human Papillomavirus RNA and DNA In Situ Hybridization on College of American Pathologists Proficiency Tests. Arch Pathol Lab Med 2019; 144:344-349. [PMID: 31483999 DOI: 10.5858/arpa.2019-0093-cp] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Detection of high-risk human papillomavirus (HR-HPV) in squamous cell carcinoma is important for classification and prognostication. In situ hybridization (ISH) is a commonly used HR-HPV-specific test that targets viral RNA or DNA. The College of American Pathologists (CAP) provides proficiency testing for laboratories performing HR-HPV ISH. OBJECTIVE.— To compare the analytical performance of RNA- and DNA-based ISH methods on CAP HR-HPV proficiency tests. DESIGN.— Data from the 2016-2018 CAP HPV ISH proficiency testing surveys were reviewed. These surveys consist of well-characterized samples with known status for HR-HPV, including 1 to 2 copies, 50 to 100 copies, 300 to 500 copies, and no copies of HR-HPV per cell. RESULTS.— Ninety-five participants submitted 1268 survey results from 20 cores. Overall, RNA ISH had a significantly higher percentage of correct responses than DNA ISH: 97.4% (450 of 462) versus 80.6% (650 of 806) (P < .001). This disparity appears to be the consequence of a superior sensitivity of RNA ISH compared to DNA ISH for samples with 1 to 2 and with 50 to 100 copies of HR-HPV per cell: 95.2% (120 of 126) versus 53.8% (129 of 240), P < .001, respectively, and 100% (89 of 89) versus 76.3% (119 of 156), P < .001, respectively. CONCLUSIONS.— An assessment of CAP HR-HPV proficiency test performance indicates that RNA ISH shows significantly higher accuracy than DNA ISH owing to higher analytical sensitivity of RNA ISH in tumors with low (1-2 copies per cell) to intermediate (50-100 copies per cell) HR-HPV viral copy numbers. These data support the use of RNA over DNA ISH in clinical laboratories that perform HR-HPV testing as part of their testing algorithms.
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Affiliation(s)
- Elaine S Keung
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - Rhona J Souers
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - Julia A Bridge
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - William C Faquin
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - Rondell P Graham
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - Meera R Hameed
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - James S Lewis
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - Jason D Merker
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - Patricia Vasalos
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
| | - Joel T Moncur
- From the Department of Pathology and Laboratory Medicine, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Keung); Biostatistics Department (Ms Souers) and Proficiency Testing (Ms Vasalos), College of American Pathologists, Northfield, Illinois; Division of Molecular Pathology, The Translational Genomics Research Institute (TGen)/Ashion Laboratory, Phoenix, Arizona, and the Department of Pathology & Microbiology, University of Nebraska Medical Center, Omaha (Dr Bridge); the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston (Dr Faquin); the Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota (Dr Graham); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Hameed); the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Departments of Pathology and Laboratory Medicine & Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill (Dr Merker); and Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Dr Moncur)
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Itskoviz D, Tamary H, Krasnov T, Yacobovich J, Sahar N, Zevit N, Shamir R, Ben-Bassat O, Leibovici Wiseman Y, Dickman R, Ringel Y, Dotan I, Goldberg Y, Morgenstern S, Levi Z. Endoscopic findings and esophageal cancer incidence among Fanconi Anemia patients participating in an endoscopic surveillance program. Dig Liver Dis 2019; 51:242-246. [PMID: 30249500 DOI: 10.1016/j.dld.2018.08.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 08/08/2018] [Accepted: 08/08/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS The primary clinical characteristics of Fanconi Anemia (FA) include typical physical features, progressive bone marrow failure, and an increased incidence of neoplasms, including esophageal carcinoma. Currently, there are no data regarding endoscopic findings or the interval time to malignancy in these patients. Data about the contribution of Human Papilloma Virus (HPV) to esophageal carcinoma is conflicting. Our objective is to document the upper gastrointestinal (GI) findings at baseline, document cancer incidence, and evaluate the role of HPV among these cancers. METHODS We reviewed endoscopic and clinical data of FA subjects who participated in active surveillance before cancer diagnosis. Incident esophageal cancers were stained for HPV p16 protein. RESULTS Eight FA patients were included (men 62.5%; median age at first endoscopy 20 years, median endoscopies number: 5.5). At baseline, 8/8 had endoscopic evidence for reflux esophagitis. In 3/8 the reflux esophagitis was mild and in 5/8 it was moderate or severe. During the follow up time (median time 4.5 years 2/8 developed Barrett's esophagus and 2/8 patients had incident esophageal squamous cell carcinoma during follow up, at intervals of eight and eighteen months from the previous upper endoscopy. Both cancers stained negative for HPV P16. CONCLUSIONS FA subjects have both an extremely high risk for esophageal cancer within short intervals and a very high prevalence of reflux esophagitis with various severities. Active surveillance programs in specialized centers including annual upper endoscopies should be considered in these patients.
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Affiliation(s)
- David Itskoviz
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Hannah Tamary
- Pediatrics Hematology Unit, Schneider's Children Medical Center, Petach Tikva, Israel; Genetic Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Tanya Krasnov
- Pediatric Hematology Laboratory, Felsenstein Medical Research Center, Beilinson Campus, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Joannae Yacobovich
- Pediatrics Hematology Unit, Schneider's Children Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Nadav Sahar
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Noam Zevit
- Institue of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Raanan Shamir
- Institue of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center of Israel, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Offer Ben-Bassat
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yaara Leibovici Wiseman
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Ram Dickman
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yehuda Ringel
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Iris Dotan
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yael Goldberg
- Genetic Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Sara Morgenstern
- Pathology Department, Rabin Medical Center, Petach Tikva, Israel
| | - Zohar Levi
- Gastroenterology Department, Rabin Medical Center, Petach Tikva, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
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McMullen C, Chung CH, Hernandez-Prera JC. Evolving role of human papillomavirus as a clinically significant biomarker in head and neck squamous cell carcinoma. Expert Rev Mol Diagn 2018; 19:63-70. [DOI: 10.1080/14737159.2019.1559056] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Caitlin McMullen
- Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Christine H. Chung
- Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Ou D, Adam J, Garberis I, Blanchard P, Nguyen F, Levy A, Casiraghi O, Gorphe P, Breuskin I, Janot F, Temam S, Scoazec JY, Deutsch E, Tao Y. Influence of tumor-associated macrophages and HLA class I expression according to HPV status in head and neck cancer patients receiving chemo/bioradiotherapy. Radiother Oncol 2018; 130:89-96. [PMID: 30172455 DOI: 10.1016/j.radonc.2018.08.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 07/25/2018] [Accepted: 08/07/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND PURPOSE To investigate the prognostic value of tumor-associated macrophages (TAM) and HLA class I expression according to HPV status in patients with head and neck squamous cell carcinoma treated with definitive radiotherapy combining cisplatin (CRT) or cetuximab (BRT). MATERIAL AND METHODS Ninety-five patients were enrolled. The density of CD68+ cells and CD68+ CD163+ cells (further referred as M2) in the intraepithelial and the stromal compartments, respectively, as well as HLA class I expression in tumor cells, were evaluated semi-quantitatively. Correlations between biomarker expression and treatment outcomes were analyzed. RESULTS Multivariate analysis showed that the intraepithelial macrophage density (IEMD) was prognostic for favorable progression-free survival (PFS) and there was a non-significant trend for improved overall survival (OS). HLA class I down-regulation was not an independent prognostic factor. Subgroup analysis showed that in p16+ population, patients with high IEMD had improved 5-year PFS vs. patients with low IEMD (81.2% vs. 25.0%, p < 0.001), while in p16- population, no difference was observed. Similarly, when stratified by primary tumor site, IEMD showed prognostic value in oropharyngeal cancer patients (OPC) but not non-OPC patients. Five-year PFS of patients with low stromal M2 macrophage density treated with CRT was significantly improved vs. those with BRT (54.5% vs. 36.1%, p = 0.03), while in tumors with high M2, there was no significant difference (50.3% vs. 42.9%, p = 0.67). CONCLUSIONS The prognostic role of TAM phenotype and distribution depends on HPV status and might predict treatment response. They prompt further validation in prospective studies.
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Affiliation(s)
- Dan Ou
- Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France; Université Paris Sud, France; INSERM1030 Molecular Radiotherapy, Villejuif, France; Department of Radiation Oncology, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China
| | - Julien Adam
- Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Ingrid Garberis
- Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France; INSERM US23/CNRS UMS3655, Molecular Analysis, Modelling and Imaging of Cancer Disease, Experimental and Translational Pathology, Villejuif, France
| | - Pierre Blanchard
- Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - France Nguyen
- Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Antonin Levy
- Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France; Université Paris Sud, France; INSERM1030 Molecular Radiotherapy, Villejuif, France
| | - Odile Casiraghi
- Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Philippe Gorphe
- Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Ingrid Breuskin
- Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - François Janot
- Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Stephane Temam
- Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France
| | - Jean-Yves Scoazec
- Université Paris Sud, France; Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France; INSERM US23/CNRS UMS3655, Molecular Analysis, Modelling and Imaging of Cancer Disease, Experimental and Translational Pathology, Villejuif, France
| | - Eric Deutsch
- Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France; Université Paris Sud, France; INSERM1030 Molecular Radiotherapy, Villejuif, France
| | - Yungan Tao
- Department of Radiation Oncology, Gustave Roussy Cancer Campus, Villejuif, France; Université Paris Sud, France; INSERM1030 Molecular Radiotherapy, Villejuif, France.
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Yang H, Cao Y, Li ZM, Li YJ, Jiang WQ, Shi YX. The role of protein p16 INK4a in non-oropharyngeal head and neck squamous cell carcinoma in Southern China. Oncol Lett 2018; 16:6147-6155. [PMID: 30333880 DOI: 10.3892/ol.2018.9353] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 08/03/2018] [Indexed: 12/16/2022] Open
Abstract
Cyclin-dependent kinase inhibitor 2A (p16INK4a) protein is a surrogate immunohistochemical marker of human papillomavirus infection in oropharynx squamous cell carcinoma (OPSCC). However, the effects of p16INK4a in non-OPSCC require additional analysis. In addition, major gaps remain in the literature, including small volumes of data for China. Therefore, the present study evaluated the frequency of p16INK4a positivity in patients with non-OPSCC in Southern China, and assessed its prognostic value. p16INK4a expression status in patients with non-OPSCC was determined by immunohistochemistry. p16INK4a-positive expression was defined as a strong and diffuse staining in ≥70% of the tumor cells. Then, the diagnostic value of p16INK4a in predicting overall survival (OS) and disease-free survival (DFS) rate was determined. The positive rate of p16INK4a was 26.3% in larynx cancer and 24.8% in oral cavity cancer. Multivariate analysis revealed that the protein status independently predicted improved OS rate, but not DFS rate (P=0.096). Comparing different disease stages, patients at an early stage with p16INK4a-positive non-OPSCC exhibited improved DFS and OS rates compared with those exhibited by patients who were negative. The p16INK4a-positive rate in patients with non-OPSCC was 25.1% [26.3% in Laryngeal squamous cell carcinoma (LSCC) and 24.8% in Oropharyngeal squamous cell carcinomas (OSCC)] in the present cohort from South China. The present study suggested that p16INK4a expression in non-OPSCC predicts favorable clinical outcomes, particularly in early stage non-OPSCC and oral cancer.
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Affiliation(s)
- Hang Yang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Ye Cao
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.,Clinical Trial Center, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Zhi-Ming Li
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Ya-Jun Li
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.,Department of Lymphoma and Hematology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
| | - Wen-Qi Jiang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
| | - Yan-Xia Shi
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
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HPV E6 oncoproteins and nucleic acids in neck lymph node fine needle aspirates and oral samples from patients with oropharyngeal squamous cell carcinoma. PAPILLOMAVIRUS RESEARCH 2018; 6:1-5. [PMID: 29842928 PMCID: PMC5986165 DOI: 10.1016/j.pvr.2018.05.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 04/26/2018] [Accepted: 05/25/2018] [Indexed: 11/23/2022]
Abstract
Commercial assays measuring HPV E6 viral oncoproteins, E6/E7 mRNA or DNA were used to test neck lymph node fine needle aspirates (FNA) and oropharyngeal samples (saliva and oral swabs) from 59 Canadian patients with oropharyngeal squamous cell carcinomas (OPSCC). Overall agreements of p16 antigen staining of tumors to FNA tested for OncoE6™, Aptima HPV E6/E7 mRNA and cobas HPV DNA were 81.4% (k 0.53), 94.9% (k 0.83) and 91.1% (k 0.73) respectively. Using HPV presence in a subset of 25 tumors as the comparator, overall agreement was 64.0% (k 0.08) with OncoE6™, 88.0% (k 0.65) with Aptima HPV E6/E7 mRNA and 91.7% (k 0.70) with cobas HPV DNA. HPV testing of oropharyngeal samples yielded lower agreements with tumor markers; 23.7-24.0% (k 0.02), 55.9-68.0% (k 0.24-0.37) and 78.9-86.9% (k 0.49-0.58) in the 3 respective tests. HPV 16 was present in 93.7-100% of the samples tested and showed 100% genotype agreement between FNA and tumors. The high rates for HPV E6 oncoproteins and E6/E7 mRNA suggests most patients were experiencing transcriptionally active HPV-related OPSCC. Results from these commercial assays performed on FNA but not oropharyngeal samples showed moderate to very good agreements with p16 and HPV testing of tumors.
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Lydiatt W, O'Sullivan B, Patel S. Major Changes in Head and Neck Staging for 2018. Am Soc Clin Oncol Educ Book 2018; 38:505-514. [PMID: 30231400 DOI: 10.1200/edbk_199697] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Oncologists should be aware of three major modifications and additions to staging head and neck cancer that became effective in 2018. Oral cavity cancers have the addition of depth of invasion; oropharyngeal cancers (OPCs) are now distinguished by the immunohistochemical stain, p16, into those that are associated with high-risk human papillomavirus and those that are not; and all sites except nasopharyngeal carcinoma and high-risk human papillomavirus OPC will now include the important parameter of extranodal extension. The rationale and emerging data supporting these changes are discussed in this article and the accompanying oral presentation at the 2018 ASCO Annual Meeting.
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Affiliation(s)
- William Lydiatt
- From the Department of Surgery, Nebraska Methodist Hospital, Creighton University, Omaha, NE; Department of Radiation Oncology, University of Toronto, Department of Otolaryngology/Head and Neck Surgery, University of Toronto, Toronto, ON, Canada; Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Brian O'Sullivan
- From the Department of Surgery, Nebraska Methodist Hospital, Creighton University, Omaha, NE; Department of Radiation Oncology, University of Toronto, Department of Otolaryngology/Head and Neck Surgery, University of Toronto, Toronto, ON, Canada; Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Snehal Patel
- From the Department of Surgery, Nebraska Methodist Hospital, Creighton University, Omaha, NE; Department of Radiation Oncology, University of Toronto, Department of Otolaryngology/Head and Neck Surgery, University of Toronto, Toronto, ON, Canada; Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
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41
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Lewis JS, Beadle B, Bishop JA, Chernock RD, Colasacco C, Lacchetti C, Moncur JT, Rocco JW, Schwartz MR, Seethala RR, Thomas NE, Westra WH, Faquin WC. Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists. Arch Pathol Lab Med 2018; 142:559-597. [PMID: 29251996 DOI: 10.5858/arpa.2017-0286-cp] [Citation(s) in RCA: 385] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Context Human papillomavirus (HPV) is a major cause of oropharyngeal squamous cell carcinomas, and HPV (and/or surrogate marker p16) status has emerged as a prognostic marker that significantly impacts clinical management. There is no current consensus on when to test oropharyngeal squamous cell carcinomas for HPV/p16 or on which tests to choose. Objective To develop evidence-based recommendations for the testing, application, interpretation, and reporting of HPV and surrogate marker tests in head and neck carcinomas. Design The College of American Pathologists convened a panel of experts in head and neck and molecular pathology, as well as surgical, medical, and radiation oncology, to develop recommendations. A systematic review of the literature was conducted to address 6 key questions. Final recommendations were derived from strength of evidence, open comment period feedback, and expert panel consensus. Results The major recommendations include (1) testing newly diagnosed oropharyngeal squamous cell carcinoma patients for high-risk HPV, either from the primary tumor or from cervical nodal metastases, using p16 immunohistochemistry with a 70% nuclear and cytoplasmic staining cutoff, and (2) not routinely testing nonsquamous oropharyngeal carcinomas or nonoropharyngeal carcinomas for HPV. Pathologists are to report tumors as HPV positive or p16 positive. Guidelines are provided for testing cytologic samples and handling of locoregional and distant recurrence specimens. Conclusions Based on the systematic review and on expert panel consensus, high-risk HPV testing is recommended for all new oropharyngeal squamous cell carcinoma patients, but not routinely recommended for other head and neck carcinomas.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - William C Faquin
- From the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Lewis); the Department of Radiation Oncology, Stanford University Medical Center, Palo Alto, California (Dr Beadle); the Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland (Drs Bishop and Westra); the Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri (Dr Chernock); Surveys, the College of American Pathologists, Northfield, Illinois (Mss Colasacco and Thomas); Policy and Advocacy, American Society of Clinical Oncology, Alexandria, Virginia (Ms Lacchetti); the Department of Pathology, Walter Reed National Military Medical Center, Bethesda, Maryland (Dr Moncur); the Department of Otolaryngology-Head and Neck Surgery, Ohio State University Wexler Medical Center, Columbus (Dr Rocco); the Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas (Dr Schwartz); the Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (Dr Seethala); and the Department of Pathology, Massachusetts General Hospital, Boston (Dr Faquin)
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42
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Augustin J, Outh-Gauer S, Mandavit M, Gasne C, Grard O, Denize T, Nervo M, Mirghani H, Laccourreye O, Bonfils P, Bruneval P, Veyer D, Péré H, Tartour E, Badoual C. Evaluation of the efficacy of the 4 tests (p16 immunochemistry, polymerase chain reaction, DNA, and RNA in situ hybridization) to evaluate a human papillomavirus infection in head and neck cancers: a cohort of 348 French squamous cell carcinomas. Hum Pathol 2018; 78:63-71. [PMID: 29684499 DOI: 10.1016/j.humpath.2018.04.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/06/2018] [Indexed: 11/26/2022]
Abstract
It is now established that human papillomavirus (HPV) plays a role in the development of a subset of head and neck squamous cell carcinomas (SCCs), notably oropharyngeal (OP) SCCs. However, it is not clear which test one should use to detect HPV in OP and non-OP SCCs. In this study, using 348 head and neck SCCs (126 OP SCCs and 222 non-OP SCCs), we evaluated diagnostic performances of different HPV tests in OP and non-OP SCCs: polymerase chain reaction, p16 immunostaining, in situ hybridization targeting DNA (DNA-CISH) and RNA (RNA-CISH), combined p16 + DNA-CISH, and combined p16 + RNA-CISH. HPV DNA (polymerase chain reaction) was detected in 26% of all tumors (44% of OP SCCs and 17% of non-OP SCCs). For OP SCCs, RNA-CISH was the most sensitive stand-alone test (88%), but p16 + RNA-CISH was even more sensitive (95%). Specificities were the same for RNA-CISH and DNA-CISH (97%), but it was better for p16 + RNA-CISH (100%). For non-OP SCCs, all tests had sensitivities less than 50%, and RNA-CISH, DNA-CISH, and p16 + DNA-CISH had 100%, 97%, and 99% specificities, respectively. As a stand-alone test, RNA-CISH is the most performant assay to detect HPV in OP SCCs, and combined p16 + RNA-CISH test slightly improves its performances. However, RNA-CISH has the advantage of being one single test. Like p16 and DNA-CISH, RNA-CISH performances are poor in non-OP SCCs to detect HPV, and combining tests does not improve performances.
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Affiliation(s)
- Jérémy Augustin
- Department of Pathology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Sophie Outh-Gauer
- Department of Pathology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Marion Mandavit
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, 75013 Paris, France.
| | - Cassandre Gasne
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Department of ENT Surgery, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Ophélie Grard
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, 75013 Paris, France.
| | - Thomas Denize
- Department of Pathology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Marine Nervo
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, 75013 Paris, France.
| | - Haïtham Mirghani
- Department of ENT Surgery, Institut Gustave Roussy, 94800 Villejuif, France.
| | - Ollivier Laccourreye
- Department of ENT Surgery, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Pierre Bonfils
- Department of ENT Surgery, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Patrick Bruneval
- Department of Pathology, Hôpital Européen Georges Pompidou, 75015 Paris, France; INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France.
| | - David Veyer
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Department of microbiology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Hélène Péré
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Department of microbiology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Eric Tartour
- INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Department of Immunology, Hôpital Européen Georges Pompidou, 75015 Paris, France.
| | - Cécile Badoual
- Department of Pathology, Hôpital Européen Georges Pompidou, 75015 Paris, France; INSERM U970, Université Paris Descartes Sorbonne Paris-Cité, 75015 Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer, 75013 Paris, France.
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Yoo M, Kim J, Bae S, Ahn S, Ahn S, Koh Y. Detection of clinically occult primary tumours in patients with cervical metastases of unknown primary tumours: comparison of three-dimensional THRIVE MRI, two-dimensional spin-echo MRI, and contrast-enhanced CT. Clin Radiol 2018; 73:410.e9-410.e15. [DOI: 10.1016/j.crad.2017.10.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 10/25/2017] [Indexed: 10/18/2022]
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44
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Zhong Q, Li K, Chen D, Wang H, Lin Q, Liu W. Rapid detection and subtyping of human papillomaviruses in condyloma acuminatum using loop-mediated isothermal amplification with hydroxynaphthol blue dye. Br J Biomed Sci 2018. [PMID: 29537347 DOI: 10.1080/09674845.2017.1411864] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Objective Condyloma acuminatum (CA) is a common, viral, sexually transmitted disease worldwide. Human papillomavirus (HPV) genotyping has important clinical implications for the treatment of CA. We developed a loop-mediated isothermal amplification (LAMP) method for the detection of HPV. Methods We collected 294 cervical scrape samples, including 30 HPV-6-positive, 30 HPV-11-positive, 22 HPV-16-positive, 20 HPV-42-positve, 30 HPV-43-positive, 20 HPV-44-positive and 142 HPV-negative samples. Tissues from 40 patients with a pathological diagnosis of CA were paraffin-embedded and analyzed by LAMP and Luminex. Hydroxynaphthol blue (HNB) and electrophoresis were used to detect the results of LAMP. Results LAMP and Luminex systems were compared in detecting six subtypes of HPV. LAMP reactions were specific for each subtype. The sensitivity of LAMP for HPV-6, as determined by the HNB indicator assay, was 1000 copies/tube. The kappa value between the two methods was 0.98 (HPV-6), 0.94 (HPV-11), 0.89 (HPV-43), 0.87 (HPV-42) 0.79 (HPV-16) and 0.68 (HPV-44). Among the 142 HPV-negative samples determined by the Luminex assay, HPV-6 was detected in eight and HPV-11 in one by LAMP. Among the 40 CA samples, the results of LAMP and Luminex were in agreement in 38 (95%). Conclusion The results of this study indicated that the LAMP assay with HNB is superior to the Luminex method in terms of sensitivity and specificity. The specificity of LAMP was 100% and the sensitivity of LAMP was 1000 copies/tube using HNB. LAMP is therefore a useful, quick and accurate method for the clinical diagnosis of HPV subtypes.
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Affiliation(s)
- Q Zhong
- a Department of Central Laboratory , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China.,b Department of Laboratory Medicine , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China.,c Department of Laboratory Medicine , Shanghai Skin Disease Hospital, Tongji University , Shanghai , China
| | - K Li
- a Department of Central Laboratory , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China.,b Department of Laboratory Medicine , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - D Chen
- a Department of Central Laboratory , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China.,b Department of Laboratory Medicine , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - H Wang
- d Department of Laboratory Medicine , Huashan Hospital, Fudan University , Shanghai , China
| | - Q Lin
- e Department of Radiation Oncology , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - W Liu
- a Department of Central Laboratory , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China.,b Department of Laboratory Medicine , Shanghai Tenth People's Hospital, Tongji University , Shanghai , China.,c Department of Laboratory Medicine , Shanghai Skin Disease Hospital, Tongji University , Shanghai , China
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Götz C, Drecoll E, Straub M, Bissinger O, Wolff KD, Kolk A. Impact of HPV infection on oral squamous cell carcinoma. Oncotarget 2018; 7:76704-76712. [PMID: 27732948 PMCID: PMC5363542 DOI: 10.18632/oncotarget.12501] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 09/13/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Head and neck squamous cell carcinomas (HNSCC) are often divided by their aetiology. Noxae associated collectives are compared with the human papilloma virus (HPV)-associated group, whereas different localisations of oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas are mostly discussed as one single group. Our aim was to show that classification by aetiology is not appropriate for OSCC. RESULTS HPV DNA was detected by PCR in 7 (3.47%) patients, and we identified 12 (5.94%) positive (+) cases by p16INK4a immunostaining. Only 4 (1.98%) of the p16INK4a+ cases were + for HPV using PCR. Our homogenous collective of OSCC allowed us to compare HPV+ and HPV negative (-) patients without creating bias for tumour localisation, age, gender or tumour stage. MATERIALS AND METHODS After testing OSCC samples for HPV positivity, we compared the results of two commonly used HPV detection methods, p16INK4a immunostaining and HPV DNA-related PCR, on 202 OSCC patients. HPV subtypes were determined with an HPV LCD Array Kit. Clinicopathological features of the patients were analysed, and the disease specific survival rates (DSS) for HPV+ and HPV- patients were obtained. CONCLUSIONS p16INK4a immunostaining is a not a reliable HPV detection method for OSCC. Positive p16INK4a immunostaining did not agree with + results from PCR of HPV DNA. Furthermore, the influence of HPV-related oncogenic transformation in OSCC is overestimated. The significance of HPV infection remains clinically unclear, and its influence on survival rates is not relevant to OSCC cases.
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Affiliation(s)
- Carolin Götz
- Department of Maxillofacial and Oral Surgery, Technical University Munich, 81675 München, Germany
| | - Enken Drecoll
- Department of Pathology, Technical University Munich, 81675 München, Germany
| | - Melanie Straub
- Department of Pathology, Technical University Munich, 81675 München, Germany
| | - Oliver Bissinger
- Department of Maxillofacial and Oral Surgery, Technical University Munich, 81675 München, Germany
| | - Klaus-Dietrich Wolff
- Department of Maxillofacial and Oral Surgery, Technical University Munich, 81675 München, Germany
| | - Andreas Kolk
- Department of Maxillofacial and Oral Surgery, Technical University Munich, 81675 München, Germany
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Dok R, Abbasi Asbagh L, Van Limbergen EJ, Sablina A, Nuyts S. Nuclear p16INK4a expression predicts enhanced radiation response in head and neck cancers. Oncotarget 2018; 7:38785-38795. [PMID: 27246975 PMCID: PMC5122429 DOI: 10.18632/oncotarget.9609] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 04/29/2016] [Indexed: 02/02/2023] Open
Abstract
Immunohistochemistry analysis of p16INK4a in head and neck squamous cell carcinomas (HNSCC) tumor samples revealed that 28% of tumors showed nuclear/cytoplasmic p16INK4a localization, while 37% of tumors had cytoplasmic p16INK4a. Our previous study showed that p16INK4a inhibits the DNA repair response independently of its function in the cell cycle, suggesting that p16INK4a subcellular localization should be considered during stratification of HNSCC patients. Using p16INK4a mutants with different localization signals, we found that expression of nuclear p16INK4a, but not cytoplasmic p16INK4a impaired RAD51 foci formation, indicating that nuclear localization of p16INK4a is crucial for its function in DNA repair. We next investigated the role of p16INK4a subcellular localization in radiation response in a retrospective cohort of 261 HNSCC patients treated with chemoradiation. We found that only HNSCC patients expressing nuclear p16INK4a expression showed better outcome, locoregional control and disease free survival, after chemoradiation. In concordance with the patient data, only expression of nuclear p16INK4a increased radiosensitivity of HNSCC cells. These results implicate nuclear p16INK4a expression as a potent marker to predict radiation response of HNSCC patients and should be taken into account in intensification or de-escalation studies.
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Affiliation(s)
- Rüveyda Dok
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, Leuven, Belgium
| | - Layka Abbasi Asbagh
- VIB Center for the Biology of Disease, Leuven, Belgium.,Department of Human Genetics, KU Leuven, University of Leuven, Leuven, Belgium
| | - Evert Jan Van Limbergen
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, Leuven, Belgium.,Department of Radiation Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium.,Current address: Maastro Clinic, Maastricht, The Netherlands
| | - Anna Sablina
- VIB Center for the Biology of Disease, Leuven, Belgium.,Department of Human Genetics, KU Leuven, University of Leuven, Leuven, Belgium
| | - Sandra Nuyts
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, Leuven, Belgium.,Department of Radiation Oncology, Leuven Cancer Institute, UZ Leuven, Leuven, Belgium
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Thankappan K, Subramaniam N, Anand A, Balasubramanian D, Iyer S. Implementing American Joint Committee on Cancer 8th edition for head-and-neck cancer in India: Context, feasibility, and practicality. Indian J Cancer 2018; 55:4-8. [DOI: 10.4103/ijc.ijc_475_17] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
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Zhao YJ, Sun WP, Peng JH, Deng YX, Fang YJ, Huang J, Zhang HZ, Wan DS, Lin JZ, Pan ZZ. Programmed death-ligand 1 expression correlates with diminished CD8+ T cell infiltration and predicts poor prognosis in anal squamous cell carcinoma patients. Cancer Manag Res 2017; 10:1-11. [PMID: 29296096 PMCID: PMC5739110 DOI: 10.2147/cmar.s153965] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective Increased expression of programmed death-ligand 1 (PD-L1) on tumor cells can be found in various malignancies; however, very limited information is known about its role in anal squamous cell carcinoma (ASCC). This study explored PD-L1 expression in ASCC patients and its association with patients' clinicopathological features, CD8+ T cell infiltration, and prognosis. Methods Formalin-fixed paraffin-embedded tumor samples from 26 patients with ASCC were retrieved. The levels of PD-L1 expression on the membrane of both tumor cells and tumor-infiltrating mononuclear cells (TIMCs) were evaluated by immunohistochemistry. CD8+ T cell densities, both within tumors and at the tumor-stromal interface, were also analyzed. Baseline clinicopathological characteristics, human papilloma virus (HPV) status, and outcome data correlated with PD-L1-positive staining. Results PD-L1 expression on tumor cells and TIMCs was observed in 46% and 50% of patients, respectively. Nineteen patients (73%) were HPV positive, with 7 showing PD-L1-positive staining on tumor cells and 9 showing PD-L1-positive staining on TIMCs. Increasing CD8+ density within tumors, but not immune stroma, was significantly associated with decreased PD-L1 expression by both tumor cells and TIMCs (P=0.0043 and P=0.0007). Patients with negative PD-L1 expression had significantly better progression-free survival (P=0.038 and P=0.0443) and a non-statistically significant trend toward longer overall survival (P=0.0882 and P=0.1222) compared with patients with positive PD-L1 expression. Conclusion PD-L1 is widely expressed on the membrane of tumor cells and TIMCs in ASCCs. Its negative impact on prognosis may be due to the diminished CD8+ T cell infiltration within tumors.
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Affiliation(s)
- Yu-Jie Zhao
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Wei-Peng Sun
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University
| | - Jian-Hong Peng
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Yu-Xiang Deng
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Yu-Jing Fang
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Jun Huang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University
| | - Hui-Zhong Zhang
- Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - De-Sen Wan
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Jun-Zhong Lin
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
| | - Zhi-Zhong Pan
- Department of Colorectal Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center
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Belobrov S, Cornall AM, Young RJ, Koo K, Angel C, Wiesenfeld D, Rischin D, Garland SM, McCullough M. The role of human papillomavirus in p16-positive oral cancers. J Oral Pathol Med 2017; 47:18-24. [PMID: 29024035 DOI: 10.1111/jop.12649] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2017] [Indexed: 01/11/2023]
Abstract
BACKGROUND The aim of this study was to identify the presence and frequency of human papillomavirus (HPV) nucleic acid in p16-positive oral squamous cell carcinomas (OSCCs), to assess whether the virus was transcriptionally active and to assess the utility of p16 overexpression as a surrogate marker for HPV in OSCC. METHODS Forty-six OSCC patients treated between 2007 and 2011 with available formalin-fixed paraffin-embedded (FFPE) specimens were included. Twenty-three patients were positive for p16 by immunohistochemistry (IHC) and these were matched with 23 patients with p16-negative tumours. Laser capture microdissection of the FFPE OSCC tissues was undertaken to isolate invasive tumour tissue. DNA was extracted and tested for high-risk HPV types using a PCR-ELISA method based on the L1 SPF10 consensus primers, and a real-time PCR method targeting HPV-16 and HPV-18 E6 region. Genotyping of HPV-positive cases was performed using a reverse line blot hybridization assay (Inno-LiPA). RNAScope® (a chromogenic RNA in situ hybridization assay) was utilized to detect E6/E7 mRNA of known high-risk HPV types for detection of transcriptionally active virus. RESULTS HPV DNA was found in 3 OSCC cases, all of which were p16 IHC-positive. Two cases were genotyped as HPV-16 and one as HPV-33. Only one of the HPV-16 cases was confirmed to harbour transcriptionally active virus via HPV RNA ISH. CONCLUSION We have shown that the presence of transcriptionally active HPV rarely occurs in OSCC and that p16 is not an appropriate surrogate marker for HPV in OSCC cases. We propose that non-viral mechanisms are responsible for the majority of IHC p16 overexpression in OSCC.
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Affiliation(s)
- Simone Belobrov
- Melbourne Dental School, Faculty of Medicine Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Australia
| | - Alyssa M Cornall
- Regional HPV Labnet Reference Laboratory, Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Melbourne, VIC, Australia.,Murdoch Childrens Research Institute, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, VIC, Australia
| | - Richard J Young
- Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Kendrick Koo
- Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia
| | - Christopher Angel
- Department of Anatomical Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - David Wiesenfeld
- Melbourne Dental School, Faculty of Medicine Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Australia.,Department of Surgery, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia.,Head and Neck Oncology Tumour Stream, Victorian Comprehensive Cancer Centre, Melbourne, VIC, Australia
| | - Danny Rischin
- Divison of Cancer Medicine, Peter MacCallum Cancer Centre and The University of Melbourne, Melbourne, VIC, Australia
| | - Suzanne M Garland
- Regional HPV Labnet Reference Laboratory, Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Melbourne, VIC, Australia.,Murdoch Childrens Research Institute, Melbourne, VIC, Australia.,Department of Obstetrics and Gynaecology, The University of Melbourne, Melbourne, VIC, Australia
| | - Michael McCullough
- Melbourne Dental School, Faculty of Medicine Dentistry and Health Science, The University of Melbourne, Melbourne, VIC, Australia
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Lucas-Roxburgh R, Benschop J, Lockett B, van den Heever U, Williams R, Howe L. The prevalence of human papillomavirus in oropharyngeal cancer in a New Zealand population. PLoS One 2017; 12:e0186424. [PMID: 29049330 PMCID: PMC5648183 DOI: 10.1371/journal.pone.0186424] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Accepted: 09/29/2017] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND The incidence of oropharyngeal cancer (OPC) in New Zealand (NZ) has more than doubled over the last 14 years with 126 cases in 2010. Overseas studies have shown that human papillomavirus (HPV) plays a significant role in the development of these cancers. However, the role of HPV in OPC and the burden on the NZ health system is unclear. AIM The aim of the study was to determine the prevalence and the genotypes of HPV associated with OPC in New Zealand. METHODS In this study, 621 OPC were identified from cancer registry data from 1996-98, 2003-05, and 2010-12. Biopsies of 267 cases were then retrieved from laboratories throughout New Zealand. p16 immunohistochemistry and a human beta globin PCR were performed on all specimens. HPV genotyping was performed on all beta globin positive specimens using real-time PCR with melt analysis. RESULTS Using a p16/PCR algorithm, 77.9% (95% CI: 71.1-83.5%) of cases were attributable to HPV. Of these, 98.5% were HPV 16 positive. There was also one case each of HPV 33 and 35. The percentage of HPV positive cases increased from 61.9% (95% CI: 40.9%- 79.2%) in 1996-98 to 87.5% (95% CI: 79.8%- 92.5%) in 2010-12. Results from the multivariable model, adjusted for sex and ethnicity found statistically significant associations between HPV positivity and timeframe (OR: 5.65, 95% CI: 2.60-12.30, 2010-12 vs 1996-98), and between HPV positivity and patient age (OR: 0.55, 95% CI: 0.33-0.99, ≥61 years vs ≤60 years). CONCLUSIONS This data is consistent with data from other developed countries showing an increase in cases of HPV positive OPC in New Zealand, and the majority of cases being attributable to HPV 16. These results support the recent inclusion of males into the nationally funded immunization schedule for Gardasil® 9.
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Affiliation(s)
- Rebecca Lucas-Roxburgh
- Institute of Veterinary, Animal, and Biomedical Sciences, Massey University, Palmerston North, New Zealand
- * E-mail:
| | - Jackie Benschop
- Molecular Epidemiology and Public Health Laboratory, Hopkirk Research Institute, Massey University, Palmerston North, New Zealand
| | - Bruce Lockett
- Histopathology Department, MedLab Central Ltd, Palmerston North, New Zealand
| | | | - Ruth Williams
- Histopathology Department, MedLab Central Ltd, Palmerston North, New Zealand
| | - Laryssa Howe
- Institute of Veterinary, Animal, and Biomedical Sciences, Massey University, Palmerston North, New Zealand
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