p16 expression in oropharyngeal cancer: its impact on staging and prognosis compared with the conventional clinical staging parameters

Fischer, Claude; Kampmann, Martin; Zlobec, Inti; Green, E.; Tornillo, Luigi; Lugli, Alessandro; Wolfensberger, Markus; Terracciano, Luigi

doi:10.1093/annonc/mdq210

Cited by 108 publications

(99 citation statements)

References 23 publications

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“…Overexpression of p16 was observed in the present tumor specimens, confirming the results of a number of previous studies (4,(32)(33)(34)(35)(36), as well as demonstrating the strong association between p16 and HPV-infection in tonsillar carcinomas. The majority of these specimens exhibited p16 expression of medium intensity, while a further 11% showed strong p16 expression.…”

supporting

confidence: 92%

Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus

et al. 2015

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Abstract. The incidence rate of tonsillar cancer is increasing worldwide. The current study identifies a parallel increase in the incidence of tonsillar cancer, human papilloma virus (HPV) and p16 expression among a population from northern Sweden, a sparsely populated area, confirming the strong association between p16 and HPV infection in tonsillar tissue. Data from the Swedish Cancer Registry was assessed to identify cases of tonsillar cancer in the northern territorial area of Sweden. HPV DNA was extracted from paraffin embedded diagnostic biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of p16 was identified by immunochemistry. Patients were grouped into urban or rural residence categories. A total of 214 cases were identified, comprising 155 (72.4%) men and 59 (27.6%) women, and 65 of these patients, who presented between 2000 and 2012, were analyzed. The overall median age for the analyzed patients was 58 years; 48 (74%) were males (median age, 57.5 years) and 17 (26%) were females (median age, 65 years). Of the 65 specimens, 59 (91%) were positive for HPV, and 62 (95%) expressed p16. The incidence of tonsillar cancer in the cohort demonstrated a 2-fold increase between 1990 and 2013; specifically, a 2.7-fold increase was observed in men whilst the female group exhibited only a small increase. These findings demonstrate a strong association between p16 expression and HPV infection in tonsillar malignancies. The incidence of HPV-positive tonsillar cancer has increased in recent years, even in sparsely populated regions, as demonstrated in northern Sweden.

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confidence: 92%

Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus

et al. 2015

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“…needed. [10][11][12]19,20 Here, we used RPA to explore new stage groupings for HPV-positive OPC and found that incorporation of NPC N categories resulted in better distribution of patients between groups than did use of the traditional OPC N categories.…”

Section: Discussionmentioning

confidence: 99%

“…Others have similarly found that T category but not N category predicts survival for patients with HPV-positive OPC. 10,19,21,22 In an analysis of Surveillance, Epidemiology, and End Results data, Keane et al 13 found that the effect of T category on head and neck cancer-specific mortality increased between 1997 and 2008 (P for interaction = .01), whereas the effect of N category declined during this same period (P for interaction , .001), and overall stage was not predictive of outcome. 13 Similarly, Ward et al 10 retrospectively analyzed 266 patients with OPC and found that the TNM system adequately staged patients with HPV-negative but not HPV-positive disease.…”

Section: Discussionmentioning

confidence: 99%

Proposed Staging System for Patients With HPV-Related Oropharyngeal Cancer Based on Nasopharyngeal Cancer N Categories

Dahlstrom

Garden

William

et al. 2016

JCO

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Purpose Patients with human papillomavirus (HPV)–related oropharyngeal cancer (OPC) generally present with more advanced disease but have better survival than patients with HPV-unrelated OPC. The current American Joint Commission on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM staging system for OPC was developed for HPV-unrelated OPC. A new staging system is needed to adequately predict outcomes of patients with HPV-related OPC. Patients and Methods Patients with newly diagnosed HPV-positive OPC (by p16 immunohistochemistry or in situ hybridization) treated at our institution from January 2003 through December 2012 were included. By using recursive partitioning analysis (RPA), we developed new stage groupings with both traditional OPC regional lymph node (N) categories and nasopharyngeal carcinoma (NPC) N categories. Survival was estimated by the Kaplan-Meier method, and the relationship between stage and survival was examined by using Cox proportional hazards regression analysis. Results A total of 661 patients with HPV-positive OPC met the inclusion criteria. With the traditional TNM staging system, there was no difference in survival between stages (P = .141). RPA with NPC N categories resulted in more balanced stage groups and better separation between groups for 5-year survival than RPA with traditional OPC N categories. With the stage groupings that were based in part on NPC N categories, the risk of death increased with increasing stage (P for trend < .001), and patients with stage III disease had five times the risk of death versus patients with stage IA disease. Conclusion New stage groupings that are based on primary tumor (T) categories and NPC N categories better separate patients with HPV-positive OPC with respect to survival than does the current AJCC/UICC TNM staging system. Although confirmation of our findings in other patient populations is needed, we propose consideration of NPC N categories as an alternative to the traditional OPC N categories in the new AJCC/UICC TNM staging system that is currently being developed.

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“…CDKN2a/INK4a located on 9p21 is frequently inactivated in oral epithelial pre-cancer and cancer via the following events: LOH, hypermethylation, deletion, mutation. The loss of p16INK4A expression defines a subgroup of oropharyngeal cancer patients with worse clinical outcome [16] whereas p16 protein over-expression has been proposed as surrogate marker of HPV infection initially in cervical cancer by Amortegui et al, [25,26], followed by squamous cell carcinomas from other sites than uterine cervix [27], and especially in Head and Neck Cancers [28,29].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization

Pannone

Rodolico

Santoro

et al. 2012

Infectious Agents and Cancer

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Background: Recent emerging evidences identify Human Papillomavirus (HPV) related Head and Neck squamous cell carcinomas (HN-SCCs) as a separate subgroup among Head and Neck Cancers with different epidemiology, histopathological characteristics, therapeutic response to chemo-radiation treatment and clinical outcome. However, there is not a worldwide consensus on the methods to be used in clinical practice. The endpoint of this study was to demonstrate the reliability of a triple method which combines evaluation of: 1. p16 protein expression by immunohistochemistry (p16-IHC); 2. HPV-DNA genotyping by consensus HPV-DNA PCR methods (Consensus PCR); and 3 viral integration into the host by in situ hybridization method (ISH). This triple method has been applied to HN-SCC originated from oral cavity (OSCC) and oropharynx (OPSCC), the two anatomical sites in which high risk (HR) HPVs have been clearly implicated as etiologic factors. Methylation-Specific PCR (MSP) was performed to study inactivation of p16-CDKN2a locus by epigenetic events. Reliability of multiple methods was measured by Kappa statistics. Results: All the HN-SCCs confirmed HPV positive by PCR and/or ISH were also p16 positive by IHC, with the latter showing a very high level of sensitivity as single test (100% in both OSCC and OPSCC) but lower specificity level (74% in OSCC and 93% in OPSCC). Concordance analysis between ISH and Consensus PCR showed a faint agreement in OPSCC ( = 0.38) and a moderate agreement in OSCC ( = 0.44). Furthermore, the addition of double positive score (ISHpositive and Consensus PCR positive) increased significantly the specificity of HR-HPV detection on formalin-fixed paraffin embedded (FFPE) samples (100% in OSCC and 78.5% in OPSCC), but reduced the sensitivity (33% in OSCC and 60% in OPSCC). The significant reduction of sensitivity by the double method was compensated by a very high sensitivity of p16-IHC detection in the triple approach.

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p16 expression in oropharyngeal cancer: its impact on staging and prognosis compared with the conventional clinical staging parameters

Abstract: p16 is the most relevant prognostic marker in OPSCC and should be considered for inclusion into the official staging system of HNSCC.

Cited by 108 publications

References 23 publications

Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus

Incidence of tonsillar cancer in northern Sweden: Impact of human papilloma virus

Proposed Staging System for Patients With HPV-Related Oropharyngeal Cancer Based on Nasopharyngeal Cancer N Categories

Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization

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