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      Prognostic factors for head and neck cancer of unknown primary including the impact of human papilloma virus infection

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          Abstract

          Background

          Head and neck cancer of unknown primary (HNCUP) is rare and prospective studies are lacking. The impact of different prognostic factors such as age and N stage is not completely known, the optimal treatment is not yet established, and the reported survival rates vary. In the last decade, human papilloma virus (HPV) has been identified as a common cause of and important prognostic factor in oropharyngeal cancer, and there is now growing interest in the importance of HPV for HNCUP. The aim of the present study on curatively treated HNCUP was to investigate the prognostic importance of different factors, including HPV status, treatment, and overall survival.

          Methods

          A search for HNCUP was performed in the Swedish Cancer Registry, Western health district, between the years 1992–2009. The medical records were reviewed, and only patients with squamous cell carcinoma or undifferentiated carcinoma treated with curative intent were included. The tumor specimens were retrospectively analyzed for HPV with p16 immunostaining.

          Results

          Sixty-eight patients were included. The mean age was 59 years. The majority were males, and had N2 tumors. Sixty-nine percent of the tumors were HPV positive using p16 staining. Patients who were older than 70 years, patients with N3-stage tumors, and patients with tumors that were p16 negative had a significantly worse prognosis. The overall 5-year survival rate for patients with p16-positive tumors was 88% vs 61% for p16-negative tumors. Treatment with neck dissection and postoperative radiation or (chemo) radiation had 81 and 88% 5-year survival rates, respectively. The overall and disease-free 5-year survival rates for all patients in the study were 82 and 74%.

          Conclusions

          Curatively treated HNCUP had good survival. HPV infection was common. Independent prognostic factors for survival were age over 70 years, HPV status and N3 stage. We recommend that HPV analysis should be performed routinely for HNCUP. Treatment with neck dissection and postoperative radiation or (chemo) radiation showed similar survival rates.

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          Most cited references32

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          The interplay between HPV and host immunity in head and neck squamous cell carcinoma.

          Anne Andersen, Anne Sophie Koldjaer Sølling, Therese Ovesen … (2014)
          Persistent infection with human papillomavirus (HPV) type 16 is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal squamous cell carcinoma (OPSCC). The oropharyngeal epithelium differs from the mucosal epithelium at other commonly HPV16-infected sites (i.e., cervix and anogenital region) in that it is juxtaposed with the underlying lymphatic tissue, serving a key immunologic function in the surveillance of inhaled and ingested pathogens. Therefore, the natural history of infection and immune response to HPV at this site may differ from that at other anatomic locations. This review summarizes the literature concerning the adaptive immune response against HPV in the context of HNSCC, with a focus on the T-cell response. Recent studies have shown that a broad repertoire of tumor-infiltrating HPV-specific T-cells are found in nearly all patients with HPV-positive tumors. A systemic response is found in only a proportion of these. Furthermore, the local response is more frequent in OPSCC patients than in cervical cancer patients and HPV-negative OPSCC patients. Despite this, tumor persistence may be facilitated by abnormalities in antigen processing, a skewed T-helper cell response, and an increased local prevalence of T-regulatory cells. Nonetheless, the immunologic profile of HPV-positive vs. HPV-negative HNSCC is associated with a significantly better outcome, and the HPV-specific immune response is suggested to play a role in the significantly better response to therapy of HPV-positive patients. Immunoprofiling may prove a valuable prognostic tool, and immunotherapy trials targeting HPV are underway, providing hope for decreasing treatment-related toxicity.
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            Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology.

            Per Jakobsen, Kirsten Johansen, Florian C. Grau … (2000)
            The management of patients with cervical lymph node metastases from unknown primary tumours is a major challenge in oncology. This study presents data collected from all five oncology centres in Denmark. Of the 352 consecutive patients with squamous cell or undifferentiated tumours seen from 1975 to 1995, a total of 277 (79%) were treated with radical intent. The general treatment policy at all centres during the entire study period has been to treat all suitable candidates with radiotherapy to both sides of the neck and include elective irradiation of the mucosal sites in nasopharynx, and larynx, hypopharynx and larynx (81%). Irradiation of the ipsilateral neck only was done in 26 patients (10%). Radical surgery was the only treatment in 23 N1-N2 patients (9%). The 5-year estimates of neck control, disease-specific survival and overall survival for radically treated patients were 51, 48 and 36%, respectively. The emergence of the occult primary was observed in 66 patients (19%). About half of the emerging primaries were within the head and neck region with oropharynx, hypopharynx and oral cavity being the most common sites. Emerging primaries outside the head and neck region were primarily located in the lung (19 patients) and oesophagus (five patients). The frequency of emerging primary in the head and neck was significantly higher in patients treated with surgery alone, the actuarial risks at 5-year being 54+/-1% (no RT) vs. 15+/-3% (with RT), P<0.0001. The most important factor for neck control was nodal stage (5-year estimates 69% (N1), 58% (N2) and 30% (N3)). Other important parameters for neck control and disease-specific survival included haemoglobin, gender and overall treatment time. Patients treated with ipsilateral radiotherapy had a relative risk of recurrence in the head and neck region of 1.9 compared with patients treated to both neck and mucosa. At 5 years, the estimated control rates were 27% (ipsilateral) and 51% (bilateral; P=0.05). The 5-year disease-specific survival estimates were 28 and 45%, respectively (P=0.10). This study has confirmed that patients with neck node metastases from occult head and neck cancer have clinical features and prognosis similar to other head and neck malignancies. Extensive irradiation to both sides of the neck and the mucosa in the entire pharyngeal axis and larynx resulted in significantly less loco-regional failures compared with patients treated with ipsilateral techniques, but only a trend towards better survival. A prospective randomized trial is required to determine the optimal strategy in terms of locoregional control, survival and morbidity.
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              Systemic and local human papillomavirus 16-specific T-cell immunity in patients with head and neck cancer.

              M Heusinkveld, R Briet, H Gelderblom … (2012)
              Squamous cell carcinomas of the head and neck (HNSCC), in particular those of the oropharynx, can be caused by human papilloma virus Type 16 (HPV16). Whereas these HPV-induced oropharyngeal carcinomas may express the HPV16 E6 and E7 oncoproteins and are associated with better survival, the nonvirally induced HNSCC are associated with overexpression of p53. In this study we assessed the presence of systemic and local T cells reactive against these oncoproteins in HNSCC. An exploratory study on the presence, type and function of HPV16- and/or p53-specific T cells in the blood, tumor and/or metastatic lymph node as measured by several immune assays was performed in an unselected group of 50 patients with HNSCC. Tumor tissue was tested for HPV DNA and the overexpression of p53 protein. Almost all HPV16+ tumors were located in the oropharynx. Circulating HPV16- and p53-specific T cells were found in 17/47 and 7/45 tested patients. T cells were isolated from tumor cultures and/or lymph nodes of 20 patients. HPV16-specific T cells were detected in six of eight HPV+ tumors, but in none of the 12 HPV-tumors. Tumor-infiltrating p53-specific T cells were not detected. In depth analysis of the HPV16-specific T-cell response revealed that this response comprised a broad repertoire of CD4+ T-helper Type 1 and 2 cells, CD4+ regulatory T cells and CD8+ T cells reactive to HPV16. The local presence of HPV16-specific T-cell immunity in HPV16-induced HNSCC implicates a role in the antitumor response and support the development of immunotherapy for HNSCC. Copyright © 2011 UICC.
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                Author and article information

                Contributors
                Lars Axelsson:
                ORCID: http://orcid.org/0000-0001-7868-4375
                +46313429126 , +46707350038 , lars.axelsson@vgregion.se
                Journal
                Journal ID (nlm-ta): J Otolaryngol Head Neck Surg
                Journal ID (iso-abbrev): J Otolaryngol Head Neck Surg
                Title: Journal of Otolaryngology - Head & Neck Surgery
                Publisher: BioMed Central (London )
                ISSN (Print): 1916-0208
                ISSN (Electronic): 1916-0216
                Publication date (Electronic): 10 June 2017
                Publication date PMC-release: 10 June 2017
                Publication date Collection: 2017
                Volume: 46
                Electronic Location Identifier: 45
                Affiliations
                [1 ]Department of Otorhinolaryngology - Head and Neck Surgery, University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden
                [2 ]ISNI 000000009445082X, GRID grid.1649.a, Department of Oncology, , Sahlgrenska University Hospital, ; Göteborg, Sweden
                [3 ]Department of Otorhinolaryngology, Norra Älvsborgs Hospital, Trollhättan, Sweden
                [4 ]ISNI 0000 0004 0624 0275, GRID grid.413652.7, Department of Otorhinolaryngology, , Central Hospital Skövde, ; Skövde, Sweden
                [5 ]ISNI 000000009445082X, GRID grid.1649.a, Department of Clinical Pathology and Genetics, , Sahlgrenska University Hospital, ; Göteborg, Sweden
                Author information
                http://orcid.org/0000-0001-7868-4375
                Article
                Publisher ID: 223
                DOI: 10.1186/s40463-017-0223-1
                PMC ID: 5466757
                PubMed ID: 28601094
                SO-VID: 2cbec2ec-2f7e-4e6f-b5e4-15fcc85d9e58
                Copyright © © The Author(s). 2017
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 15 December 2016
                Date accepted : 26 May 2017
                Funding
                Funded by: The Foundation ACTA-Otolaryngologica
                Funded by: The Assar Gabrielssons Foundation
                Funded by: The ALF Funding for Research
                Funded by: The Health and Medical Care Committee of the Regional Executive Board, Region Västra Götaland
                Categories
                Subject: Original Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2017

                Keywords: head and neck cancer,unknown primary,human papilloma virus,p16,prognostic factors,treatment
                Data availability:
                Keywords: head and neck cancer, unknown primary, human papilloma virus, p16, prognostic factors, treatment

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