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Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-1
Umeå University, Faculty of Medicine, Department of Medical Biosciences. Naples, Italy.
Dundee, U.K..
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
Umeå University, Faculty of Medicine, Department of Medical Biosciences.
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2015 (English)In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 113, no 2, 321-326 p.Article in journal (Refereed) Published
Abstract [en]

Background: Tongue squamous cell carcinoma (TSCC) is increasing in incidence, especially among young patients and preferably females. Infection with human papilloma virus (HPV) has been suggested as a cause of SCC in the head and neck, and the proportion of oropharyngeal cancers caused by HPV has steadily increased. Methods: Samples from 109 patients with primary TSCC were analysed for the presence of HPV16 by in situ hybridisation and for expression of its surrogate marker p16 and the HPV receptor syndecan-1 by immunhistochemistry. Results: No evidence of HPV16 DNA was observed in the tumours, although one-third showed p16 staining. There was no difference in the expression of the primary HPV receptor, syndecan-1, between TSCC and a group of tonsil SCC. Conclusion: Whereas p16 is expressed in some TSCCs, HPV16 is undetectable, therefore, p16 cannot be used as a surrogate marker for high-risk HPV-infection in this tumour. Despite presence of the HPV-receptor syndecan-1 in TSCC, HPV prefers the tonsillar environment. Lack of p16 associates with worse prognosis primarily in patients aged <= 40 years with tongue SCC. The improved prognosis seen in p16-positive TSCC can be due to induction of a senescent phenotype or an inherent radiosensitivity due to the ability of p16 to inhibit homologous recombination repair.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015. Vol. 113, no 2, 321-326 p.
Keyword [en]
squamous cell carcinoma, tongue, HPV, p16, syndecan-1, TRE S, 1995, JOURNAL OF CLINICAL PATHOLOGY, V48, P876 galdi M., 2012, JOURNAL OF ORAL PATHOLOGY & MEDICINE, V41, P16 aturvedi Anil K., 2011, JOURNAL OF CLINICAL ONCOLOGY, V29, P4294
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-106780DOI: 10.1038/bjc.2015.207ISI: 000357947800017PubMedID: 26057450OAI: oai:DiVA.org:umu-106780DiVA: diva2:847803
Available from: 2015-08-21 Created: 2015-08-07 Last updated: 2017-12-04Bibliographically approved
In thesis
1. Human papillomavirus in recurrent respiratory papillomatosis, tonsillar and mobile tongue cancer
Open this publication in new window or tab >>Human papillomavirus in recurrent respiratory papillomatosis, tonsillar and mobile tongue cancer
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on the effects of the human papillomavirus (HPV) in tonsillar cancer, mobile tongue cancer, and recurrent respiratory papillomatosis (RRP). The purpose was to characterize patients with RRP in northern Sweden in order to identify more care-intensive RRP patients and to describe the voice and quality of life aspects that follow RRP. Further aims were to confirm the expected increase of HPV-positive tonsillar cancer cases in northern Sweden, and to study the correlation between HPV, its surrogate marker p16 and HPV receptor syndecan-1 in both tonsillar cancer and mobile tongue cancer.

A total of 27 consecutive patients with RRP were evaluated at 3 months postoperatively using the voice handicap index (VHI) and SF-36 questionnaires to assess the impact on life and voice in a RRP population. The values were compared to normative data. This report was further extended by examining consecutive data from 21 new patients in order to characterize RRP patients in northern Sweden. In order to study HPV DNA in tonsillar (n= 65) and mobile tongue cancer (n=109), HPV DNA was extracted from paraffin-embedded biopsies and detected by polymerase chain reaction using general primers Gp5+/6+ and CpI/IIG. Expression of HPV surrogate marker p16 and the HPV receptor syndecan-1 was analysed by immunohistochemistry.

Patients that underwent more than one RRP surgery per year were younger than those treated less frequently and they had significantly impaired voice quality as compared to normal subjects. Females, patients with frequent surgical treatment sessions, and patients with the high-risk HPV subtypes scored significantly lower in several domains of the quality of life assessment as compared with normal subjects. Forty-eight RRP patients had a median age of 44.5 years; 71% were men and 29% females, preferentially infected with HPV6. Patients with high surgical treatment frequency/year showed more widespread RRP in the larynx compared to the patients treated less frequently.

A total of 214 tonsillar cancer cases were identified. The vast majority were men. They had a median age of 58 years at diagnosis and expressed HPV as well as p16. The incidence of tonsillar cancer revealed a 2,7-fold increase in men between the years 1990 and 2013. The study demonstrates a strong association between p16 and HPV infection in tonsillar malignancies. These findings are in contrast to the mobile tongue cancer cases, where no evidence of HPV DNA could be detected although one-third showed p16 staining. This demonstrated a poor correlation between HPV and p16 in mobile tongue cancer. There was no difference in the expression of the primary HPV receptor, syndecan-1, between tonsillar and mobile tongue cancer.

In conclusion, the frequency of RRP operations, age at onset, gender and subtype of the HPV may be used as factors to predict voice disability. RRP patients with high surgical treatment frequency were significantly younger and had a more widespread laryngeal disease compared to the low-frequency treated group. This study confirms the existence of a clinical RRP group, not primarily related to HPV subtype, but to a more care-intensive RRP population. Our findings identify a 2,7-fold increase in the incidence of tonsillar cancer, HPV and p16 in men between 1990-2013. We can use p16 to detect HPV in tonsillar cancer but not in tongue cancer.

The introduction of vaccination against HPV may have a role in the prevention of specific HPV-subtype positive head and neck malignancies and recurrent respiratory papillomatosis since the current vaccine protects against HPV6, 11, 16, 18, 31, 33, 45, 52 and 58. Males will definitely benefit indirectly from vaccination of females, though males will still remain at risk of cancers associated with HPV. This highlights the need for sex-neutral vaccination strategy. Our intention is that this thesis will provide scientific data to support a gender-neutral vaccination and to develop simple tools to detect HPV in tonsillar cancer.

Abstract [sv]

Syftet med avhandlingen är att beskriva effekterna av humant papillomvirus (HPV) vid cancer i halsmandlarna, cancer i tungan och vid luftvägspapillom.

Totalt 27 patienter med luftvägspapillom (RRP) under åren 2004-2012 utvärderades 3 månader efter operationen med röst handikapp index (VHI) och livskvalitetformuläret SF-36. Resultaten jämfördes med normal data. Studiematerialet utökades med 21 patienter till totalt 48 RRP patienter i syfte att karakterisera patientgruppen i norra Sverige. För att studera HPV-DNA i tonsillcancer (n = 65) och i cancer i mobil del av tungan (n = 109) extraherades HPV-DNA från paraffininbäddade provbitar som sedan analyserades med PCR teknik och GP5 + / 6 + och CPI/IIG primer. Uttryck av surrogatmarkör p16 och HPV-receptorn syndekan -1 analyserades med immunhistokemi.

RRP patienter hade en medianålder på 44,5 år; 71% var män och 29% kvinnor, företrädesvis infekterade med HPV6. Patienter som opererades mer än en gång per år var yngre än de som behandlats mindre ofta och hade en statistiskt sämre röstkvalitet än friska kontroller. Kvinnor, patienter med täta kirurgiska behandlingsintervall och högrisk-HPV hade signifikant sämre livskvalitet jämfört med friska kontroller. Patienter med hög kirurgisk behandlingsfrekvens per år var signifikant yngre och hade mer utbredd RRP sjukdom i luftstrupen, jämfört med gruppen med låg behandlingsfrekvens.

Sammanlagt, 214 fall av halsmandelscancer identifierades i norra Sverige under åren 1990-2013; majoriteten var män, med en medianålder på 58 år och positiva för både HPV och p16. Andelen halsmandelscancer fall ökade med 2,7 gånger bland männen på 23 år. Vi fann ett starkt samband mellan uttryck av p16 och HPV infektion i halsmandelscancer men inte i HPV-negativ, delvis p16-positiv (33%) mobil tungcancer. Det fanns ingen skillnad i uttrycket av den primära HPV-receptorn, syndekan -1, jämförande tung-, och halsmandelscancer.

Antalet RRP operationer, ålder vid insjuknandet, kön och genetisk variant av HPV kan användas som indikatorer för att förutsäga grad av röststörning. RRP patienter med hög kirurgisk behandlingsfrekvens var signifikant yngre och hade en mer utbredd luftvägssjukdom jämfört med RRP patienter som behandlas mindre ofta. Vi har identifierat en undergrupp av RRP patienter som inte primärt karakteriseras efter HPV virusets genetik utan av ett mer vårdintensivt förlopp. Den aktuella avhandlingen har identifierat en 2,7-faldig ökning av antalet halsmandelscancer hos män och ett starkt samband mellan p16 och HPV infektion i halsmandlar men inte i HPV-negativ tungcancer som inte korrelerar till p16 uttryck. Vi kan använda p16 för att påvisa HPV i tonsillcancer men inte i cancer i mobil tunga.

Idag ingår HPV vaccination i det allmänna vaccinationsprogrammet för flickor. Vi förväntar oss en tydlig profylaktisk effekt avseende insjuknande i HPV-relaterad huvud- och hals cancer samt luftvägspapillom eftersom vaccinet skyddar mot HPV bl.a. 6, 11, 16 och 18. Män kommer definitivt att gynnas indirekt genom vaccination av kvinnor men kommer att ha fortsatt högre risk än kvinnor att insjukna i HPV relaterad cancer vilket understryker behovet av könsneutral vaccination. Vår avsikt med avhandlingen är att ge vetenskapligt stöd för könsneutralt vaccination och enkla metoder att påvisa halsmandelscancer.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2016. 79 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1790
Keyword
Human papillomavirus, recurrent respiratory papillomatosis tonsillar cancer, mobile tongue cancer, voice-, and quality of life, p16, syndecan-1, northern Sweden
National Category
Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-124792 (URN)978-91-7601-509-4 (ISBN)
External cooperation:
Public defence
2016-10-21, Föreläsningssalen ÖNH, by 1B plan 3, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-08-30 Created: 2016-08-25 Last updated: 2016-08-30Bibliographically approved
2. Squamous cell carcinoma of the oral tongue: studies of biomarkers connected to human papillomavirus infection, epithelial to mesenchymal transition and locoregional metastatis
Open this publication in new window or tab >>Squamous cell carcinoma of the oral tongue: studies of biomarkers connected to human papillomavirus infection, epithelial to mesenchymal transition and locoregional metastatis
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Oral Tongue Squamous Cell Carcinoma (OTSCC) is the most frequent and aggressive carcinoma in the head and neck region. Its incidence has increased during the last decades, especially in young patients (40 years) mainly female. These young patients have either not been exposed to the traditional risk factors for this disease, or have a much reduced duration of exposure than the typical OTSCC patient. The reasons behind this increasing incidence remain unknown.

The aims of this thesis were to analyse the presence and possible role of human papillomavirus (HPV) in oral tongue cancer in correlation with its surrogate marker p16 and its receptor syndecan-1. Other aims were to evaluate expression of EMT (epithelial to mesenchymal transition) - related markers, such as E-cadherin, β-catenin, CK5 and CK19, and to address the potential predictive role of podoplanin in the loco-regional metastatic process.

Clinical parameters including age, sex, geographical distribution, relapse, tumour staging and grading were also investigated for a possible correlation with biomarker expression and prediction of survival rate and therapeutic strategy.

Materials and methods: More than one hundred samples of OTSCC coming from two University Hospitals of two different countries (Sweden and Italy) were analysed. HPV presence was evaluated by in situ hybridisation for detection of the high-risk HPV 16 and indirectly by immunohistochemistry (IHC) of its surrogate marker p16. Expression of the HPV receptor syndecan-1 and the EMT biomarkers E-cadherin, β-catenin, CK5, CK19 were also evaluated by immunohistochemistry.

Samples were scored using a quick score (QS), taking both number and intensity of cells stained into account. Podoplanin expression was investigated at both protein and RNA level.

Results: Tumour size and lymph node metastasis correlated to both overall and disease-free survival. Despite variable expression of the syndecan-1 receptor, HPV 16 was not detected in any sample analysed, excluding a possible association with p16, which was expressed in 33% of the cases.

All EMT-related markers were commonly expressed in tongue cancer. Data showed E-cadherin to be an independent prognostic factor with higher expression associated with poor overall survival. Notably, E-cadherin, β-catenin and CK5 directly correlated to each other.

Multivariate analysis of clinical data demonstrated that age of the patient is an independent prognostic factor with younger patients showing a worse survival rate. Patients younger than 40 years also showed significantly higher expression of podoplanin. Data for geographic distribution revealed a difference in expression of E-cadherin between Swedish and Italian patients.

Conclusions: In contrast to SCC of the base of the tongue and the tonsil, HPV is not present in OTSCC, excluding HPV infection as a risk factor. Higher levels of E-cadherin and young age is associated with poor survival in OTSCC patients. The different frequency of EMT markers seen between Swedish and Italian patients suggests an important role for the environment and the geographical area in the onset of different molecular patterns of OTSCC.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 89 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1888
Keyword
squamous cell carcinoma oral tongue, p16, HPV, podoplanin, E-cadherin
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:umu:diva-134567 (URN)978-91-7601-720-3 (ISBN)
Public defence
2017-06-02, Betula, Byggnad 6M, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Cancer Society, 16 03 36Västerbotten County Council
Available from: 2017-05-05 Created: 2017-05-09 Last updated: 2017-05-11Bibliographically approved

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Sgaramella, NicolaStrindlund, K.Loljung, LottaLoizou, ChristosOlofsson, KatarinaDanielsson, KarinNylander, Karin
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