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Kühn JP, Schmid W, Körner S, Bochen F, Wemmert S, Rimbach H, Smola S, Radosa JC, Wagner M, Morris LG, Bozzato V, Bozzato A, Schick B, Linxweiler M. HPV Status as Prognostic Biomarker in Head and Neck Cancer-Which Method Fits the Best for Outcome Prediction? Cancers (Basel) 2021; 13:cancers13184730. [PMID: 34572957 PMCID: PMC8469433 DOI: 10.3390/cancers13184730] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/11/2021] [Accepted: 09/20/2021] [Indexed: 01/22/2023] Open
Abstract
The incidence of human papillomavirus (HPV)-related head and neck cancer (HNSCC) is rising globally, presenting challenges for optimized clinical management. To date, it remains unclear which biomarker best reflects HPV-driven carcinogenesis, a process that is associated with better therapeutic response and outcome compared to tobacco/alcohol-induced cancers. Six potential HPV surrogate biomarkers were analyzed using FFPE tissue samples from 153 HNSCC patients (n = 78 oropharyngeal cancer (OPSCC), n = 35 laryngeal cancer, n = 23 hypopharyngeal cancer, n = 17 oral cavity cancer): p16, CyclinD1, pRb, dual immunohistochemical staining of p16 and Ki67, HPV-DNA-PCR, and HPV-DNA-in situ hybridization (ISH). Biomarkers were analyzed for correlation with one another, tumor subsite, and patient survival. P16-IHC alone showed the best performance for discriminating between good (high expression) vs poor outcome (low expression; p = 0.0030) in OPSCC patients. Additionally, HPV-DNA-ISH (p = 0.0039), HPV-DNA-PCR (p = 0.0113), and p16-Ki67 dual stain (p = 0.0047) were significantly associated with prognosis in uni- and multivariable analysis for oropharyngeal cancer. In the non-OPSCC group, however, none of the aforementioned surrogate markers was prognostic. Taken together, P16-IHC as a single biomarker displays the best diagnostic accuracy for prognosis stratification in OPSCC patients with a direct detection of HPV-DNA by PCR or ISH as well as p16-Ki67 dual stain as potential alternatives.
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Affiliation(s)
- Jan Philipp Kühn
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Wendelin Schmid
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Sandrina Körner
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Florian Bochen
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Silke Wemmert
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Hugo Rimbach
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Sigrun Smola
- Institute of Virology, Saarland University Medical Center, D-66421 Homburg, Germany;
| | - Julia Caroline Radosa
- Department of Gynecology and Obstetrics, Saarland University Medical Center, D-66421 Homburg, Germany;
| | - Mathias Wagner
- Department of General and Surgical Pathology, Saarland University Medical Center, D-66421 Homburg, Germany;
| | - Luc G.T. Morris
- Immunogenomics and Precision Oncology Platform, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Victoria Bozzato
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Alessandro Bozzato
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Bernhard Schick
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
| | - Maximilian Linxweiler
- Department of Otorhinolaryngology, Saarland University Medical Center, D-66421 Homburg, Germany; (J.P.K.); (W.S.); (S.K.); (F.B.); (S.W.); (H.R.); (V.B.); (A.B.); (B.S.)
- Correspondence: ; Tel.: +49-6841-1622928
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Oncological outcome following initiation of treatment for stage III and IV HPV negative oropharyngeal cancers with transoral robotic surgery (TORS). Eur J Surg Oncol 2019; 45:2137-2142. [DOI: 10.1016/j.ejso.2019.06.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/02/2019] [Accepted: 06/18/2019] [Indexed: 01/26/2023] Open
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Ziai H, Alenazi A, Hearn M, O'Connell DA, Puttagunta L, Barber B, Harris JR, Seikaly H, Biron VL. The association of Bcl-xL and p53 expression with survival outcomes in oropharyngeal cancer. Cancer Biomark 2019; 24:141-151. [PMID: 30614804 DOI: 10.3233/cbm-182106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND The role of molecular biomarkers in oropharyngeal squamous cell carcinoma (OPSCC) has recently been increasingly recognized. There is conflicting evidence in the literature with regards to the prognostic value of p53 and Bcl-xL. OBJECTIVE The purpose of this study was to investigate the association between p53 and Bcl-xL expression profiles and survival outcomes in OPSCC. METHODS Patients diagnosed with OPSCC and treated with curative intent between 1998 and 2009 were included in the study. Patient demographics, disease, treatment, and oncologic outcomes were collected prospectively. A tissue microarray (TMA) from patients' biopsies or surgical specimens was retrospectively constructed. The expression levels of p53, Bcl-xL, and p16 were digitally quantified and correlated to patient survival outcomes. RESULTS One hundred and sixty-six patients were included (mean age 56.7 years; standard deviation (SD) ± 10.0; 78% male). High expression of Bcl-xL (p= 0.04) was significantly associated with nodal disease at presentation, and decreased overall survival (OS) (p= 0.04). Combined expression of low Bcl-xL and low p53 conferred a survival advantage in non-smokers (p= 0.04). Multivariate analysis supported smoking and p16 status as independent prognosticators for OS. CONCLUSIONS This study suggests that biomarker profiling using Bcl-xL and p53 levels may be of prognostic value in select patients with OPSCC.
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Affiliation(s)
- Hedyeh Ziai
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Abdulrahman Alenazi
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Matthew Hearn
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Daniel A O'Connell
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Lakshmi Puttagunta
- Department of Laboratory Medicine and Pathology, University of Alberta, University of Alberta Hospital, Edmonton, AB, Canada
| | - Brittany Barber
- Department of Otolaryngology-Head and Neck Surgery, University of Washington Medical Center, Seattle, WA, USA
| | - Jeffrey R Harris
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Hadi Seikaly
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Vincent L Biron
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
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Gheit T, Anantharaman D, Holzinger D, Alemany L, Tous S, Lucas E, Prabhu PR, Pawlita M, Ridder R, Rehm S, Bogers J, Maffini F, Chiocca S, Lloveras B, Kumar RV, Somanathan T, de Sanjosé S, Castellsagué X, Arbyn M, Brennan P, Sankaranarayanan R, Pillai MR, Gangane N, Tommasino M. Role of mucosal high-risk human papillomavirus types in head and neck cancers in central India. Int J Cancer 2017; 141:143-151. [PMID: 28369859 DOI: 10.1002/ijc.30712] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2016] [Revised: 02/17/2017] [Accepted: 03/07/2017] [Indexed: 01/21/2023]
Abstract
Mucosal high-risk (HR) human papillomaviruses (HPV) cause a subset of head and neck cancers (HNC). The HPV-attributable fraction of HNC varies substantially between countries. Although HNC has a very high incidence in the Indian subcontinent, information on the contribution of HPV infection is limited. Here, we evaluated the HPV-attributable fraction in HNC (N = 364) collected in a central region of India. HNC from three different anatomical subsites were included, namely, oral cavity (n = 252), oropharynx (n = 53) and hypopharynx/larynx (n = 59). In this retrospective study, HPV-driven HNC were defined by presence of both viral DNA and RNA. Overexpression of p16INK4a was also evaluated. HR-HPV DNA was detected in 13.7% of the cases; however, only 2.7% were positive for both HPV DNA and RNA. The highest percentage of HPV DNA/RNA double positivity was found in oropharynx (9.4%), followed by larynx (1.7%) and oral cavity (1.6%) (p = 0.02). More than half of HPV DNA/RNA-positive cases were p16INK4a -negative, while a considerable number of HPV RNA-negative cases were p16INK4a -positive (17.9%). HPV16 was the major type associated with HNC (60.0%), although cases positive for HPV18, 35 and 56 were also detected. Our data indicate that the proportion and types of mucosal HR-HPV associated with HNC in this central Indian region differ from those in other (developed) parts of the world. This may be explained by differences in smoking and/or sexual behaviour compared with North America and northern Europe. Moreover, we show that p16INK4a staining appeared not to be a good surrogate marker of HPV transformation in the Indian HNC cases.
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Affiliation(s)
- Tarik Gheit
- International Agency for Research on Cancer, Lyon, 69008, France
| | - Devasena Anantharaman
- International Agency for Research on Cancer, Lyon, 69008, France
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, 695014, India
| | - Dana Holzinger
- Deutsches Krebsforschungszentrum (DKFZ), 69120, Heidelberg, Germany
| | - Laia Alemany
- L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain & CIBER Epidemiologia y Salud Publica, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - Sara Tous
- L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain & CIBER Epidemiologia y Salud Publica, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - Eric Lucas
- International Agency for Research on Cancer, Lyon, 69008, France
| | - Priya Ramesh Prabhu
- Rajiv Gandhi Centre for Biotechnology, Poojappura, Thiruvananthapuram, Kerala, 695014, India
| | - Michael Pawlita
- Deutsches Krebsforschungszentrum (DKFZ), 69120, Heidelberg, Germany
| | - Ruediger Ridder
- Roche MTM laboratories, Mannheim, Germany
- Ventana Medical Systems Inc, Tucson, AZ
| | | | | | | | | | - Belén Lloveras
- Hospital del Mar, Parc de Salut Mar, Pg/Marítim 25-29, Barcelona, 08003, Spain
| | - Rekha Vijay Kumar
- Kidwai Memorial Institute of Oncology, Bangalore, Karnataka, 560029, India
| | | | - Silvia de Sanjosé
- L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain & CIBER Epidemiologia y Salud Publica, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - Xavier Castellsagué
- L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain & CIBER Epidemiologia y Salud Publica, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO)-IDIBELL, Barcelona, Spain
| | - Marc Arbyn
- Unit of Cancer Epidemiology/Belgian Cancer Centre, Scientific Institute of Public Health, Brussels, B1050, Belgium
| | - Paul Brennan
- International Agency for Research on Cancer, Lyon, 69008, France
| | | | | | - Nitin Gangane
- Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha, Maharashtra State, 442102, India
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Oncological outcome following de-intensification of treatment for stage I and II HPV negative oropharyngeal cancers with transoral robotic surgery (TORS): A prospective trial. Oral Oncol 2017; 69:80-83. [DOI: 10.1016/j.oraloncology.2017.04.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 03/14/2017] [Accepted: 04/13/2017] [Indexed: 11/23/2022]
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Human Papilloma Virus in Oral Cavity Cancer and Relation to Change in Quality of Life Following Treatment-a Pilot Study from Northern India. Indian J Surg Oncol 2016; 7:386-391. [PMID: 27872524 DOI: 10.1007/s13193-016-0559-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 09/06/2016] [Indexed: 01/09/2023] Open
Abstract
Human papilloma virus (HPV)-associated head and neck cancer (HNC) has generated significant amount of research interest in recent times with focus shifted to oral cavity squamous cell cancer (OCSCC) after oropharyngeal cancer. Due to high incidence of OCSCC and anecdotal reports on association of HPV infection from northern region of India, this study was conceived to investigate HPV infection and establish its association with lifestyle habits such as tobacco, alcohol consumption, oro-genital sex, number of sexual contacts, and change in quality of life posttreatment. A total of 43 primary OCSCC biopsy specimens were collected. These samples were analyzed for HPV DNA genotyping which was done by using 13 high-risk HPV real-time PCR kits. Quality of life was assessed using University of Washington questionnaire for HNC patients, which was administered pretreatment and 3-months posttreatment. HPV presence was confirmed in only three patients (7.0 %). HPV positivity did not find any statistical correlation with age, gender, residence, addiction habit, stage, tumor size, nodal status, tumor grade, and number of sexual contacts. There was no significant (p > 0.05) difference in the average percent change in QOL parameters from pretreatment to posttreatment when correlated with HPV status.
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Shaikh MH, McMillan NAJ, Johnson NW. HPV-associated head and neck cancers in the Asia Pacific: A critical literature review & meta-analysis. Cancer Epidemiol 2015; 39:923-38. [PMID: 26523982 DOI: 10.1016/j.canep.2015.09.013] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 09/14/2015] [Accepted: 09/28/2015] [Indexed: 11/26/2022]
Abstract
BACKGROUND Malignancies of the upper aero-digestive tract are a major public health problem, especially in the Asia Pacific. Certain Human papillomaviruses (HPVs) are well-established risk factors for carcinoma of the uterine cervix and for a subset of head and neck carcinomata: however their true importance in different populations and anatomical subsites remains unclear. The major risk factors in Asia Pacific remain smoked/smokeless tobacco, areca nut, alcohol abuse and poor diet, with limited evidence for HPVs. We review published studies of association of HPV with anatomical site-specific Head & Neck Squamous Cell Carcinoma (HNSCC) in these populations and attempt a meta-analysis. MATERIALS AND METHODS From MEDLINE/PubMed/WEB-of SCIENCE/EMBASE/Scopus databases we found 67 relevant studies with a total of 7280 cases: 15 case-control studies met our inclusion criteria for meta-analysis, totaling 1106 cases & 638 controls. HPV detection rates, sample site and size, and methods of tissue preservation and HPV detection were tabulated for each study. RESULTS Studies were heterogeneous in terms of sample selection and method of detection of HPVs. Most were of limited quality. Averaging data from 67 studies of HNSCC, the prevalence of HPV of any subtype is approximately 36%. PCR (polymerase chain reaction) was the most used detection method and HPV16 the most common genotype reported. Meta-analyses of case-control studies from this region reveal significant heterogeneity but suggest higher HPV prevalence in oropharyngeal cancer (OR: 14.66; 95%CI: 6.09-35.26) compared to oral cavity cancer and laryngeal cancer; (OR: 4.06; 95%CI: 3.05-5.39 & OR: 3.23; 95%CI: 1.37-7.61) respectively. CONCLUSION In view of the significant association of HPV with HNSCC, studies with accurate subsite classification and more sensitive detection methods are necessary. Accurate data from this geographical region are essential to inform public health policies and treatment decisions, especially as studies from Europe and North America reveal HPV-driven cancers to be less aggressive, permitting treatment de-intensification.
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Affiliation(s)
- Mushfiq Hassan Shaikh
- School of Dentistry & Oral Health, Griffith University, Gold Coast Campus, Queensland, Australia; School of Medical Science, Griffith University, Gold Coast Campus, Queensland, Australia; Cancer Research Centre, Molecular Basis of Disease program, Menzies Health Institute Queensland, Griffith University, Queensland, Australia.
| | - Nigel A J McMillan
- School of Medical Science, Griffith University, Gold Coast Campus, Queensland, Australia; Cancer Research Centre, Molecular Basis of Disease program, Menzies Health Institute Queensland, Griffith University, Queensland, Australia.
| | - Newell W Johnson
- Cancer Research Centre, Molecular Basis of Disease program, Menzies Health Institute Queensland, Griffith University, Queensland, Australia; Population & Social Health Research program, Menzies Health Institute Queensland, Griffith University, Queensland, Australia.
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Kumar R, Rai AK, Das D, Das R, Kumar RS, Sarma A, Sharma S, Kataki AC, Ramteke A. Alcohol and Tobacco Increases Risk of High Risk HPV Infection in Head and Neck Cancer Patients: Study from North-East Region of India. PLoS One 2015; 10:e0140700. [PMID: 26473489 PMCID: PMC4608822 DOI: 10.1371/journal.pone.0140700] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Accepted: 09/28/2015] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Human papilloma virus (HPV) associated Head and Neck Cancers (HNCs) have generated significant amount of research interest in recent times. Due to high incidence of HNCs and lack of sufficient data on high-risk HPV (hr-HPV) infection from North -East region of India, this study was conceived to investigate hr-HPV infection, its types and its association with life style habits such as tobacco, alcohol consumption etc. METHODS A total of one hundred and six primary HNC tumor biopsy specimens were collected. These samples were analyzed for hr-HPV DNA (13 HPV types) using hybrid capture 2 (HC2) assay and genotyping was done by E6 nested multiplex PCR (NMPCR). RESULTS The presence of hr-HPV was confirmed in 31.13% (n = 33) and 24.52% (n = 26) of the HNC patients by nested multiplex PCR (NMPCR) and HC2 assay respectively. Among hr-HPV positive cases, out of thirteen hr- HPV types analyzed, only two prevalent genotypes, HPV-16 (81.81%) followed by HPV-18 (18.18%) were found. Significant association was observed between hr-HPV infection with alcohol consumption (p <0.001) and tobacco chewing (p = 0.02) in HNC cases. Compared to HPV-18 infection the HPV-16 was found to be significantly associated with tobacco chewing (p = 0.02) habit. CONCLUSIONS Our study demonstrated that tobacco chewing and alcohol consumption may act as risk factors for hr-HPV infection in HNCs from the North-East region of India. This was the first study from North-East India which also assessed the clinical applicability of HC2 assay in HNC patient specimens. We suggest that alcohol, tobacco and hr- HPV infection act synergistically or complement each other in the process of HNC development and progression in the present study population.
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Affiliation(s)
- Rupesh Kumar
- Cancer Genetics and Chemoprevention Research Group, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, India
| | - Avdhesh Kumar Rai
- DBT center for Molecular Biology and Cancer Research, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
| | - Debabrata Das
- DBT center for Molecular Biology and Cancer Research, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
| | - Rajjyoti Das
- Department of Head and Neck Oncology, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
| | - R. Suresh Kumar
- Division of Molecular Genetics, Institute of Cytology and Preventive Oncology (ICMR), I-7, Sector 39, Noida, Uttar Pradesh, India
| | - Anupam Sarma
- Department of Pathology, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
| | - Shashi Sharma
- Division of Epidemiology and Biostatistics, Institute of Cytology and Preventive Oncology (ICMR), I-7, Sector 39, Noida, Uttar Pradesh, India
| | - Amal Chandra Kataki
- Department of Gynecologic oncology, Dr. B. Borooah Cancer Institute, Guwahati, Assam, India
| | - Anand Ramteke
- Cancer Genetics and Chemoprevention Research Group, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, India
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Scantlebury JB, Luo J, Thorstad WL, El-Mofty SK, Lewis JS. Cyclin D1-a prognostic marker in oropharyngeal squamous cell carcinoma that is tightly associated with high-risk human papillomavirus status. Hum Pathol 2013; 44:1672-80. [PMID: 23566410 DOI: 10.1016/j.humpath.2013.01.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Revised: 01/28/2013] [Accepted: 01/29/2013] [Indexed: 12/30/2022]
Abstract
Human papillomavirus-related oropharyngeal squamous cell carcinoma has a unique biology and improved prognosis. A new focus is to identify prognostic biomarkers specifically in this human papillomavirus-positive cohort. We analyzed cyclin D1 immunostaining on a tissue microarray of patients with known clinical follow-up and p16 and human papillomavirus status (by E6/E7 RNA in situ hybridization). Cyclin D1 staining was read visually and digitally. Cutoffs of 5%, 10%, and 30% were separately analyzed as was linear intensity data derived from the image analysis. For the 202 tumors, cyclin D1 expression was > 10% in 25.7% (visual) and 35.5% (digital) of the cases. It was > 30% in 15.8% (visual) and 16.5% (digital) of the cases. High cyclin D1 by both methods, cutoffs, and expression intensity was associated with poorer overall, disease-free, and disease-specific survival in univariate analysis. However, low cyclin D1 expression was also tightly associated with human papillomavirus RNA (P < 1.0 × 10(-18) for all cutoffs) and p16 positivity (P < 1.0 × 10(-14) for all cutoffs). In multivariate analysis using the digital 30% cutoff (the strongest cyclin D1 assessment method), only T stage, p16 status, smoking, and treatment approach associated with survival. Intensity of cyclin D1 expression did, however, significantly substratify the human papillomavirus RNA-positive patients into prognostic subgroups independent of other variables. In summary, cyclin D1 overexpression correlates strongly with patient survival in oropharyngeal squamous cell carcinoma, but its relationship with human papillomavirus status is very tight, and the complex nature of this correlation likely limits any clinical application for cyclin D1 assessment.
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Termine N, Giovannelli L, Rodolico V, Matranga D, Pannone G, Campisi G. Biopsy vs. brushing: comparison of two sampling methods for the detection of HPV-DNA in squamous cell carcinoma of the oral cavity. Oral Oncol 2012; 48:870-5. [PMID: 22498489 DOI: 10.1016/j.oraloncology.2012.03.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Revised: 03/02/2012] [Accepted: 03/02/2012] [Indexed: 11/16/2022]
Abstract
BACKGROUND HR HPV infection was proposed as aetiological factor of oral squamous cell carcinomas (OSCC). HPV frequency in OSCC is highly variable, due to the discrepancy in oral sampling procedures, HPV testing methods and inclusion criteria regarding tumour site (strictly oral cavity vs. nearby structures). Our aim was to compare HPV DNA frequency and type-specific distribution in paired cytological and histological samples of SCC strictly located in oral cavity. The correlation between HPV detection rate by each method of sampling and demographical, behavioural and clinical-pathological variables was also examined. PATIENTS AND METHODS HPV DNA was detected in brushed cells and formalin-fixed paraffin-embedded biopsies obtained from 83 consecutive unselected immunocompetent adults with OSCC. HPV DNA detection was performed in all samples by nPCR followed by direct DNA sequencing and the assay INNO-LiPA HPV Genotyping. Univariate and multivariate statistics were used, including Cohen κ index to evaluate agreement between two methods and association between HPV infection and demographical, behavioural and clinical-pathological variables for each method of sampling (p<0.05 statistically significant). RESULTS HPV DNA was detected in 15.7% (13/83) of brushings and 12.1% (10/83) of biopsies (p>0.05). High risk HPV 51, 16 and 39 were genotypes more frequently detected, especially among biopsies; no concordance between two methods was found (Cohen κ index=0.04, p=0.34). CONCLUSION A fraction of OSCC could be linked to HR HPV infection in the Mediterranean area. Although without a statistical significance, biopsy specimen demonstrated more accurate for HR HPV detection than brushing in OSCC.
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Affiliation(s)
- N Termine
- Section of Oral Sciences, Sector of Oral Medicine, Department of Surgical and Oncologic Disciplines, University of Palermo, Palermo, Italy
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Seraj JM, Yazdani N, Ashtiani ZO, Seraj SM, Hasheminasab SM, Memar B, Mirashrafi F, Borghei H, Yazdani J, Mostaan LV. TP53 gene expression in HPV-positive oral tongue SCC and its correlation with nodal metastasis. Pathol Res Pract 2011; 207:758-61. [PMID: 22055991 DOI: 10.1016/j.prp.2011.09.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2011] [Revised: 07/23/2011] [Accepted: 09/26/2011] [Indexed: 11/18/2022]
Abstract
In this study, we investigated the prevalence of human papilloma virus (HPV) infection and TP53 expression in patients with squamous cell carcinoma (SCC) of the tongue and, subsequently, its significance in cervical lymph node metastases and tumor differentiation. Sections of formalin-fixed, paraffin-embedded tissue blocks from 94 histologically confirmed tongue SCC cases were investigated in this study. Immunohistochemistry was used to study TP53 expression, and polymerase chain reaction (PCR) was performed for the detection of high risk HPV types (16 and 18). The frequency of HPV-16 and HPV-18 infection was 10.6% and 16%, respectively. Overexpression of TP53 was observed in 70.2% of patients. Young patients (aged below 45 years) comprised 20% of all patients. There was no significant association between TP53, HPV-16, or HPV 18 presence and higher stages of the tumor, tumor differentiation, or presence of nodal metastasis. Although an association between head and neck SCC and HPV infection is being recognized and reported, our data implicate that HPV infection or TP53 expression does not play a significant role in oral tongue SCC pathogenesis, differentiation, or metastasis, as seen in our patients.
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Affiliation(s)
- Jalal Mehdizadeh Seraj
- Otorhinolaryngology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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12
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Hannisdal K, Schjølberg A, De Angelis PM, Boysen M, Clausen OPF. Human papillomavirus (HPV)-positive tonsillar carcinomas are frequent and have a favourable prognosis in males in Norway. Acta Otolaryngol 2010; 130:293-9. [PMID: 19680990 DOI: 10.3109/00016480903071377] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONCLUSIONS This study confirms a high prevalence of human papillomavirus (HPV)-positive tonsillar tumours (52%). The survival of the HPV-positive group was significantly better in males. OBJECTIVES We assessed the prevalence of HPV in 137 patients with tonsillar carcinomas, measured the p53- and Ki-67-positive tumour cell fractions and correlated the results with clinical variables. PATIENTS AND METHODS Tumour DNA from patients with squamous cell carcinoma of the tonsillar region was amplified by PCR and sequenced for detection of HPV subtypes. RESULTS HPV was found in 71/137 (52%) of the tumours; HPV-16 was the most frequent subtype (87%). HPV positivity did not correlate with gender, stage, T- and N categories, Ki-67 expression or p53 positivity. The HPV-positive group had a significantly better survival (p < 0.01) compared with the HPV-negative group in males. In a multivariate analysis HPV status gave prognostic information in addition to the earlier established factors, i.e. age, gender and stage (p < 0.05).
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Affiliation(s)
- Kirsten Hannisdal
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery, Oslo University Hospital, Oslo, Norway.
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13
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Hafkamp HC, Mooren JJ, Claessen SMH, Klingenberg B, Voogd AC, Bot FJ, Klussmann JP, Hopman AHN, Manni JJ, Kremer B, Ramaekers FCS, Speel EJM. P21 Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis. Mod Pathol 2009; 22:686-98. [PMID: 19305381 DOI: 10.1038/modpathol.2009.23] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16(INK4A,) cyclin D1, pRb, p14(ARF), MDM2, p53, p21(Cip1/WAF1), and p27(KIP1). Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16(INK4A) overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14(ARF) (P<0.0001) and p21(Cip1/WAF1) (P=0.001), and downregulation of pRb (P<0.0001) and cyclin D1 (P=0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P=0.006), as well as for patients with T1-2 tumors (P<0.0001) or tumors showing low expression of cyclin D1 (P=0.028), presence of human papillomavirus and overexpression of p16(INK4A) (P=0.01), p14(ARF) (P=0.02) or p21(Cip1/WAF1) (P=0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21(Cip1/WAF1), were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21(Cip1/WAF1) and p14(ARF) overexpression and downregulation of pRb and cyclin D1. In particular p21(Cip1/WAF1) overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas.
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Affiliation(s)
- Harriët C Hafkamp
- Department of Otorhinolaryngology and Head and Neck Surgery, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
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14
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Termine N, Panzarella V, Falaschini S, Russo A, Matranga D, Lo Muzio L, Campisi G. HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988-2007). Ann Oncol 2008; 19:1681-1690. [PMID: 18558666 DOI: 10.1093/annonc/mdn372] [Citation(s) in RCA: 206] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/28/2024] Open
Abstract
INTRODUCTION In the literature, there exists a wide range of human papillomavirus (HPV) DNA prevalence for head and neck squamous cell carcinoma (HNSCC), especially in relation to methods of viral detection and the lesion site. We estimated the pooled prevalence of HPV DNA in biopsies of HNSCC generically grouped versus oral squamous cell carcinoma (OSCC) in relation to the method of viral DNA detection, with the primary end point of verifying if these two variables (specification of tumour site and method of HPV DNA identification) influence the datum on HPV assay. METHODS By means of MEDLINE/PubMED/Ovid databases, we selected studies examining paraffin-embedded (PE) biopsies of HNSCC and OSCC. According to the inclusion criteria, 62 studies were analyzed. The following data were abstracted: sample size, HPV DNA prevalence, methods of detection [PCR and in situ hybridization (ISH)] and HPV genotypes. After testing the heterogeneity of the studies by the Cochran Q test, metanalysis was performed using the random effects model. RESULTS The pooled prevalence of HPV DNA in the overall samples (Sigma: 4852) was 34.5%, in OSCC it was 38.1% and in the not site-specific HNSCC was 24.1%. With regard to the detection method, PCR-based studies reported a higher prevalence rate than ISH-based rates (34.8, versus 32.9%) especially in the OSCC subgroup (OSCC PCR based: 39.9%). CONCLUSION These findings support the assumption that a correct distinction of HNSCC by site, together with the use of more sensitive HPV DNA detection methods, should be considered as essential prerogatives in designing future investigations into viral prevalence in head and neck tumors.
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Affiliation(s)
- N Termine
- Department of Oral Sciences, Section of Oral Medicine, University of Palermo, Palermo, Italy
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15
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Charfi L, Jouffroy T, de Cremoux P, Le Peltier N, Thioux M, Fréneaux P, Point D, Girod A, Rodriguez J, Sastre-Garau X. Two types of squamous cell carcinoma of the palatine tonsil characterized by distinct etiology, molecular features and outcome. Cancer Lett 2007; 260:72-8. [PMID: 18060686 DOI: 10.1016/j.canlet.2007.10.028] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2007] [Revised: 10/16/2007] [Accepted: 10/17/2007] [Indexed: 10/22/2022]
Abstract
To determine whether human papillomaviruses (HPV) positive tonsillar squamous cell carcinoma (SCC) represent a specific entity, we studied the prevalence of HPV association and of tobacco/alcohol exposure in a series of 52 cases of tonsillar SCC cases. p53, p16, and pRb levels, deregulated by viral oncoproteins were assessed. Forty patients reported tobacco/alcohol exposure, 10 reported no exposure. HPV DNA was found in 32/52 (62%) cases, (HPV16 genotype in 27). All patients with no history of tobacco-alcohol exposure presented HPV positive tumor (p=0.0008). A strong correlation was observed between positive HPV status, decrease in pRB and increase in p16 expression level. 5 year overall survival rate was higher in HPV16 positive patients than in HPV negative (71% versus 36%; p=0.023). HPV status remained a significant prognostic factor in multivariate analysis. Tonsillar SCC can thus be divided in HPV positive and negative subgroups with different oncogenesis and response to treatment.
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Affiliation(s)
- Lamia Charfi
- Department of Tumor Biology, Institut Curie 26 rue d'Ulm 75248 Paris Cedex 05, France
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16
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Tran N, Rose BR, O'Brien CJ. Role of human papillomavirus in the etiology of head and neck cancer. Head Neck 2007; 29:64-70. [PMID: 16823878 DOI: 10.1002/hed.20460] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Head and neck cancer is the world's sixth most common cancer, but despite advances in treatment, there has been no significant decline in the mortality rate. In recent years, there has been mounting epidemiologic and experimental evidence of a role for human papillomavirus (HPV) as the etiologic agent of a subset of head and neck cancers. The association is strongest for oropharyngeal cancers, especially those of the tonsil. HPV 16 is invariably the predominant type. HPV-positive cancers have been shown to be biologically distinct, clustering among nonsmokers and light drinkers, and have been associated with a favorable prognosis. This review examines the current findings of HPV in head and neck cancers and discusses implications for developing new treatments.
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Affiliation(s)
- Nham Tran
- Sydney Head and Neck Cancer Institute, Sydney Cancer Centre, Royal Prince Alfred Hospital and the University of Sydney, P. O. Box M 142, Missenden Road, Camperdown NSW 2050, Australia.
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Nemes JA, Deli L, Nemes Z, Márton IJ. Expression of p16INK4A, p53, and Rb proteins are independent from the presence of human papillomavirus genes in oral squamous cell carcinoma. ACTA ACUST UNITED AC 2006; 102:344-52. [PMID: 16920543 DOI: 10.1016/j.tripleo.2005.10.069] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2005] [Revised: 11/03/2005] [Accepted: 11/04/2005] [Indexed: 01/10/2023]
Abstract
BACKGROUND The overexpression of p16(INK4A) and suppression of p53 and Rb proteins are key features of oncogenic transformation by human papillomaviruses (HPV) in anogenital cancers. HPV genomes are often detected in cancers of the oral cavity, but it is unclear whether HPV has a specific oncogenic role there. OBJECTIVES The objectives of the study were to investigate the expression of p53, Rb, and p16(INK4A) proteins and identify HPV infection and viral integration into the host genome. METHODS Seventy-nine cases of oral squamous cell carcinoma (OSCC) were studied by immunohistochemistry. Polymerase chain reaction (PCR) was performed to identify HPV DNA from the samples. The results were correlated with clinical data. RESULTS Thirty-three cases were HPV positive for high-risk HPV (HR-HPV) types, of which 27 harbored HPV16. In 25 of 27 HPV16-positive tumors, the HPV16 genome was fully integrated into the host genome, as evidenced by the lack of PCR-amplifiable E2 gene sequences. Forty-five patients were p53 overexpressing, 20 with HR-HPV-positive and 25 with HR-HPV-negative tumors. p16(INK4A) protein was overexpressed in 4 of 31 HR-HPV-positive and 9of 45 HR-HPV-negative cases. Twenty-six of 32 HR-HPV-positive and 37 of 44 HR-HPV-negative samples exhibited pRb nuclear staining. These differences between HR-HPV-positive and -negative tumors were not statistically significant. No correlation was found between these biological factors and tumor location, stage, differentiation grade, or alcohol or tobacco abuse. CONCLUSIONS A tumor immunophenotype, similar to HPV-related anogenital cancers, is not present in OSCC and highly oncogenic HPV types are therefore unlikely to be specific or independent risk factors for oral cancer.
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Affiliation(s)
- Judit A Nemes
- Faculty of Dentistry, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
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18
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Campisi G, Giovannelli L, Calvino F, Matranga D, Colella G, Di Liberto C, Capra G, Leao JC, Lo Muzio L, Capogreco M, D'Angelo M. HPV infection in relation to OSCC histological grading and TNM stage. Evaluation by traditional statistics and fuzzy logic model. Oral Oncol 2006; 42:638-45. [PMID: 16483833 DOI: 10.1016/j.oraloncology.2005.11.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2005] [Accepted: 11/10/2005] [Indexed: 11/22/2022]
Abstract
We aimed to evaluate if in oral squamous cell carcinoma (OSCC) there is a relationship between histological grading (HG), TNM clinical stage and HPV infection; and to study the performance of fuzzy logic compared to traditional statistics, in the analysis of HPV status and correlates of OSCC. In cross-sectional analysis, the study group comprised 63 patients (mean age 68.89 years (SD +/-11.78), range (32-93); males 28 (44.4%), females 35 (55.6%)) with OSCC histologically diagnosed. HPV-DNA was studied in exfoliated oral epithelial cells by nested PCR (MY09/MY11 and GP5+/GP6+ primers). Data were analysed in parallel by traditional statistics with multivariate analysis and a fuzzy logic (FL) technique (membership functions as input, the ANFIS methodology, and the Sugeno's model of first order). HPV infection was detected in 24/63 (38.1%) of OSCC, as being HPV+ve 14/36 (38.9%) in G1, 7/18 (38.9%) in G2, and 3/9 (33.3%) in G3; HPV+ve 8/33 (24.2%) in Stage I, 9/12 (75.0%) in Stage II, 6/11(54.5%) in Stage III, and 1/7 (14.3%) in Stage IV. In both methods of analysis, no significantly increased risk of HPV infection was found for any HG score; whereas, TNM stage II was significantly associated to HPV infection (p=0.004; OR=9.375 (95% CI=2.030:43.30); OR'=11.148 (95% CI=1.951:43.30)), and, in particular, to primary tumour size T2 (p=0.0036; OR=7.812 (95% CI=1.914:31.890); OR'=9.414 (95% CI=1.846:48.013)); FL (% of prevision: 79.8; Root Mean-Square Error (RMSE): 0.29). No association was found between HPV infection and any demographical variable. Our findings show an association between HPV infection with TNM (stage II-T2), but not with histological grading of OSCC. Also, FL seems to be an additional effective tool in analysing the relationship of HPV infection with correlates of OSCC.
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Affiliation(s)
- G Campisi
- Dipartimento di Scienze Stomatologiche, Università di Palermo, Via del Vespro 129, 90127 Palermo, Italy.
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Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int J Exp Pathol 2006; 86:347-63. [PMID: 16309541 PMCID: PMC2517451 DOI: 10.1111/j.0959-9673.2005.00447.x] [Citation(s) in RCA: 148] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) involves the upper aerodigestive tract and can destroy the structure and function of organs involved in voice, speech, taste, smell and hearing, as well as vital structures necessary for survival. HNSCC has long been a treatment challenge because of the high rate of recurrences and of advanced disease at the time of diagnosis. Molecular identification of tissue biomarkers in diagnostic biopsy specimens may not only identify patients at risk for developing HNSCC but may also select patients that may benefit from more aggressive treatment modalities. Several biomarkers studied to date such as the proteins p53, cyclin D1, p16, Cox-2 enzyme, epidermal growth factor and vascular endothelial growth factor receptors, matrix metalloproteinases and the Fhit marker for genomic instability could be manipulated for the therapeutic benefit of these patients. This review presents the most updated information on molecular biomarkers with the greatest prognostic potential in HNSCC and discusses some factors that contribute to the controversy concerning their prognostic importance.
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Affiliation(s)
- Giovana R Thomas
- Department of Otolaryngology-Head and Neck Surgery, University of Miami School of Medicine, Miami, FL 33136, USA.
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Leão JC, Góes P, Sobrinho CB, Porter S. Knowledge and clinical expertise regarding oral cancer among Brazilian dentists. Int J Oral Maxillofac Surg 2005; 34:436-9. [PMID: 16053856 DOI: 10.1016/j.ijom.2004.10.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2004] [Revised: 07/14/2004] [Accepted: 10/19/2004] [Indexed: 10/25/2022]
Abstract
The aim of the present work was to assess the knowledge and attitudes of Brazilian General Dental Practitioners with regard to aspects of the aetiology, early diagnosis and prevention of oral cancer relevant for general dental practice. A convenience sample of 129 dentists in Brazil was randomly selected and asked to complete a questionnaire. Results of bi-variated analysis revealed that a self-perceived good knowledge regarding relevant aspects of oral cancer was statistically significantly associated with male gender (Chi square=4.59, P<0.05). Simple logistic regression revealed that male professionals were 2.9 times more knowledgeable than their female colleagues (OR=2.9, 1.1-8.1 95% CI, P=0.037), although, this association was not statistically significant when adjusted for age using multiple regression analysis (OR=2.7, 0.9-7.5 95% CI, P=0.059). There were no significant differences in relevant knowledge and attitudes of private compared with public dentists. Importantly, General Dental Practitioners who spent more than half of time of a patient's initial consultation undertaking a clinical examination were the more likely to detect oral cancer (Chi square=4.245, P=0.039) than those who set aside little time examining their patients. It is concluded that the knowledge of dentists in Brazil regarding relevant aspects of oral cancer is suboptimal, and may not be associated with any examined social-demographic variables. Further research is required to clarify the role of continuing professional education in improving the knowledge and attitudes of dentists relevant to oral cancer in Brazil.
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Affiliation(s)
- J C Leão
- Departamento de Clinica e Odontologia Preventiva, Universidade Federal de Pernambuco, Recife, PE, Brazil.
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Ma HB, Hu HT, Di ZL, Wang ZR, Shi JS, Wang XJ, Li Y. Association of cyclin D1, p16 and retinoblastoma protein expressions with prognosis and metastasis of gallbladder carcinoma. World J Gastroenterol 2005; 11:744-7. [PMID: 15655836 PMCID: PMC4250753 DOI: 10.3748/wjg.v11.i5.744] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of cyclin D1, p16 and retinoblastoma in cancerous process of gallbladder carcinomas and to assess the relation between cyclin D1, p16, Rb and the biological characteristics of gallbladder carcinoma.
METHODS: Forty-one gallbladder carcinoma, 7 gallbladder adenoma and 14 chronic cholecystitis specimens were immunohistochemically and histopathologically investigated for the relation of cyclin D1, p16 and Rb with Nevin staging and pathologic grading.
RESULTS: The expression rates of abnormal cyclin D1 in gallbladder carcinoma (68.3%)and gallbladder adenoma(57.1%) were significantly higher than those in chronic cholecystitis (7.1%) (P<0.05). No significant difference was found both among the pathological grades G1, G2 and G3 and among Nevin stagings S1-S2, S3 and S4-S5 of gallbladder carcinoma. The positive rates of p16 (48.8%) and Rb (58.5%) in gallbladder carcinoma were significantly lower compared to those in adenoma (100.0%) and cholecystitis (100.0%) (P<0.05). The positive rates of p16 and Rb in Nevin stagings S1-S2 (80.0% and 90.0%) and S3 (46.2% and 61.5%) gallbladder carcinomas were significantly higher than those in S4-S5 (33.3% and 38.8%) (P<0.05), and those in pathologic grades G1 (54.5% and 81.8%) and G2 (50.0% and 62.5%) gallbladder carcinoma were significantly higher than those in G3 (28.6% and 35.7%) (P<0.05). The protein expression of p16 and Rb had a negative-correlation in gallbladder carcinoma (r = -0.2993, P<0.05), and this negative-correlation was correlated with Nevin staging (P<0.05). Moreover, the protein expression of p16 and cyclin D1 had a negative-correlation in gallbladder carcinoma (r = -0.9417, P<0.05).
CONCLUSION: Cyclin D1 may play a role in the early stage of gallbladder carcinoma. Mutation of p16 and Rb genes might be correlated with progression of gallbladder carcinoma. Analysis of p16 and Rb can estimate the prognosis of gallbladder carcinoma. Expression of p16 and Rb may be correlated with Nevin staging and pathologic grading in gallbladder carcinoma.
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Affiliation(s)
- Hong-Bing Ma
- Department of Oncology, Second Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, China.
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