Frequency and prognostic significance of p16INK4A protein overexpression and transcriptionally active human papillomavirus infection in laryngeal squamous cell carcinoma

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Abstract

Background:

Human papillomavirus (HPV) infection is a powerful prognostic biomarker in a subset of head and neck squamous cell carcinomas, specifically oropharyngeal cancers. However, the role of HPV in non-oropharyngeal sites, such as the larynx, remains unconfirmed.

Methods:

We evaluated a cohort of 324 laryngeal squamous cell carcinoma (LSCC) patients for the expression of p16 ^INK4A (p16) protein by immunohistochemistry (IHC) and for high-risk HPV E6 and E7 mRNA transcripts by RNA in situ hybridisation (ISH). p16 expression and HPV status were correlated with clinicopathological features and outcomes.

Results:

Of 307 patients assessable for p16 IHC, 20 (6.5%) were p16 positive. Females and node-positive patients were more likely to be p16 positive ( P<0.05). There were no other significant clinical or demographic differences between p16-positive and -negative cases. There was no difference in overall survival (OS) between p16-positive and -negative patients with 2-year survival of 79% in each group (HR=0.83, 95% CI 0.36–1.89, P=0.65). There was no statistically significant difference in failure-free survival (FFS) with 2-year FFS of 79% and 66% for p16-positive and -negative patients, respectively (HR=0.60, 95% CI 0.26–1.36, P=0.22). Only seven cases were found to be HPV RNA ISH positive, all of which were p16 IHC positive. There was no statistically significant difference in OS between patients with HPV RNA ISH-positive tumours compared with -negative tumours with 2-year survival of 86% and 71%, respectively (HR=0.76, 95% CI 0.23–2.5, P=0.65). The 2-year FFS was 86% and 59%, respectively (HR=0.62, 95% CI 0.19–2.03, P=0.43).

Conclusions:

p16 overexpression is infrequent in LSCC and the proportion of cases with high-risk HPV transcripts is even lower. There are no statistically significant correlations between p16 IHC or HPV RNA ISH status and OS or disease outcomes.

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Most cited references 29

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Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group.

Gregory Wolf, Susan Gross Fisher, Waun Hong … (1991)

We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation. Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy. After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease. These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.

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Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial.

Danny Rischin, Richard J Young, Richard Fisher … (2010)

To determine the prognostic importance of p16 and human papillomavirus (HPV) in patients with oropharyngeal cancer treated on a phase III concurrent chemoradiotherapy trial. Patients with stage III or IV head and neck squamous cell cancer were randomly assigned to concurrent radiotherapy and cisplatin with or without tirapazamine. In this substudy, analyses were restricted to patients with oropharyngeal cancer. p16 was detected by immunohistochemistry, and HPV was detected by in situ hybridization and polymerase chain reaction. Slides were available for p16 assay in 206 of 465 patients, of which 185 were eligible, and p16 and HPV were evaluable in 172 patients. One hundred six (57%) of 185 were p16-positive, and in patients evaluable for both p16 and HPV, 88 (86%) of 102 p16-positive patients were also HPV-positive. Patients who were p16-positive had lower T and higher N categories and better Eastern Cooperative Oncology Group (ECOG) performance status. p16-positive tumors compared with p16-negative tumors were associated with better 2-year overall survival (91% v 74%; hazard ratio [HR], 0.36; 95% CI, 0.17 to 0.74; P = .004) and failure-free survival (87% v 72%; HR, 0.39; 95% CI, 0.20 to 0.74; P = .003). p16 was a significant prognostic factor on multivariable analysis (HR, 0.45; 95% CI, 0.21 to 0.96; P = .04). p16-positive patients had lower rates of locoregional failure and deaths due to other causes. There was a trend favoring the tirapazamine arm for improved locoregional control in p16-negative patients (HR, 0.33; 95% CI, 0.09 to 1.24; P = .13). HPV-associated oropharyngeal cancer is a distinct entity with a favorable prognosis compared with HPV-negative oropharyngeal cancer when treated with cisplatin-based chemoradiotherapy.

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Human papillomavirus in head and neck cancer: its role in pathogenesis and clinical implications.

Paul Chung, Maura L. Gillison (2009)

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer with an annual incidence of approximately 400,000 worldwide. Although the principal risk factors for head and neck cancer remain tobacco and alcohol use, human papillomavirus (HPV) has recently been found to be etiologically associated with 20 to 25% of HNSCC, mostly in the oropharynx. HPV causes human cancers by expressing two viral oncoproteins, E6 and E7. These oncoproteins degrade and destabilize two major tumor suppressor proteins, p53 and pRb, through ubiquitination. Additional studies have shown that E6 and E7 can directly bind to multiple host proteins other than p53 and pRb (e.g., Bak and p21(Cip1)), further contributing to genetic instability. However, expression of E6 and E7 alone is not sufficient for cellular transformation, and the additional genetic alterations necessary for malignant progression in the setting of virus-induced genomic instability are unknown. In addition to the etiological differences, HPV-positive cancers are clinically distinct when compared with HPV-negative cancers with regard to treatment response and survival outcome, with tumor HPV-positivity being a favorable prognostic biomarker. Further understanding of carcinogenesis and clinical behavior of HPV-positive cancers will improve disease prevention, patient care, and surveillance strategies for HNSCC patients.

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Author and article information

Journal

Journal ID (nlm-ta): Br J Cancer

Journal ID (iso-abbrev): Br. J. Cancer

Title: British Journal of Cancer

Publisher: Nature Publishing Group

ISSN (Print): 0007-0920

ISSN (Electronic): 1532-1827

Publication date (Print): 17 March 2015

Publication date (Electronic): 17 February 2015

Volume: 112

Issue: 6

Pages: 1098-1104

Affiliations

[1 ]Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia

[2 ]Sir Peter MacCallum Department of Oncology, University of Melbourne , Melbourne, Australia

[3 ]Department of Medical Oncology, Peter MacCallum Cancer Centre , Melbourne, Australia

[4 ]Department of Pathology, Peter MacCallum Cancer Centre , Melbourne, Australia

[5 ]Department of Radiation Oncology, Peter MacCallum Cancer Centre , Melbourne, Australia

[6 ]Department of Surgery, St Vincent's Hospital , Melbourne, Australia

[7 ]Department of Otorhinolaryngology, Monash Medical Centre , Melbourne, Australia

[8 ]Department of Surgical Oncology, Peter MacCallum Cancer Centre , Melbourne, Australia

[9 ]Department of Surgery, Melbourne University, Royal Melbourne Hospital , Melbourne, Australia

Author notes

[* ]E-mail: Danny.Rischin@ 123456petermac.org

[10]

RJ Young and D Urban contributed equally to this work.

Article

Publisher Item ID: bjc201559

DOI: 10.1038/bjc.2015.59

PMC ID: 4366899

PubMed ID: 25688737

SO-VID: a5a82b11-9701-405b-be0d-f4f52b558cdd

License:

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

History

Date received : 24 September 2014

Date revision received : 18 November 2014

Date accepted : 19 January 2015

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