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Squamous cell carcinoma of the oral tongue: studies of biomarkers connected to human papillomavirus infection, epithelial to mesenchymal transition and locoregional metastatis
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. (Karin Nylander)
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 [en]
squamous cell carcinoma oral tongue, p16, HPV, podoplanin, E-cadherin
National Category
Cancer and Oncology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-134567ISBN: 978-91-7601-720-3 OAI: oai:DiVA.org:umu-134567DiVA: diva2:1094089
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
List of papers
1. Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-1
Open this publication in new window or tab >>Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-1
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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
Keyword
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:nbn:se:umu:diva-106780 (URN)10.1038/bjc.2015.207 (DOI)000357947800017 ()26057450 (PubMedID)
Available from: 2015-08-21 Created: 2015-08-07 Last updated: 2017-05-09Bibliographically approved
2. E-cadherin expression associates with poor survival in Swedish but not Italian patients with squamous cell carcinoma of the oral tongue
Open this publication in new window or tab >>E-cadherin expression associates with poor survival in Swedish but not Italian patients with squamous cell carcinoma of the oral tongue
(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-134762 (URN)
Available from: 2017-05-11 Created: 2017-05-11 Last updated: 2017-05-11
3. High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients ≤ 40 years but does not correlate with tumour spread
Open this publication in new window or tab >>High expression of podoplanin in squamous cell carcinoma of the tongue occurs predominantly in patients ≤ 40 years but does not correlate with tumour spread
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2016 (English)In: The Journal of Pathology: Clinical Research, ISSN 2056-4538, Vol. 2, no 1, 3-8 p.Article in journal (Refereed) Published
Abstract [en]

More than 30% of patients with squamous cell carcinoma (SCC) of the mobile tongue have clinically undetectable lymph node metastasis. Tumour cells can spread as single cells or collectively. A protein known to play a role in both processes is podoplanin, which is expressed in endothelial cells not only in lymph vessels but also in some aggressive tumours with high invasive and metastatic potential. Here we studied samples from 129 patients with primary SCC of the tongue for expression of podoplanin using immunohistochemistry. mRNA levels were analysed in another 27 cases of tongue SCC with adjacent clinically tumour-free tongue tissue and 14 tongue samples from healthy donors. Higher levels of podoplanin were seen in tumours compared to both normal tongue and clinically normal tongue in the tumour vicinity. No association was found between levels of podoplanin, presence of lymph node metastases or other clinical factors. Patients aged 40 or less were more likely to express high levels of podoplanin protein compared to older patients (p 50.027). We conclude that levels of podoplanin in primary tongue SCCs are not associated with lymph node metastases. However, tongue SCCs arising in young patients (40 years of age) are more likely to express high levels of podoplanin than tongue SCCs that arise in the more elderly. The data suggest that podoplanin has a distinctive role in young patients, who are known to have a poor prognosis: these patients may, therefore, benefit from podoplanin inhibitory therapies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2016
Keyword
squamous cell carcinoma, tongue, podoplanin
National Category
Cancer and Oncology Otorhinolaryngology
Identifiers
urn:nbn:se:umu:diva-121097 (URN)10.1002/cjp2.28 (DOI)
Available from: 2016-05-26 Created: 2016-05-26 Last updated: 2017-05-09Bibliographically approved

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