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Studies on the occurrence and effects of human papillomavirus in tumors of the head and neck
Institutionen för onkologi-patologi, Karolinska Institutet.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The presence of human papillomavirus (HPV) in squamous cell carcinoma of the head and neck (HNSCC) was first reported in 1985. Since then, this association has been studied intensively and today there is substantial evidence for HPV as a causative agent and positive prognostic factor for clinical outcome in tonsillar cancer, but the association to other HNSCC is still unclear. The aim of this thesis was first to examine the presence of HPV in tongue cancer and to study its possible influence on disease outcome. Thereafter, the association between HPV and cdk inhibitor p16INK4a expression and a possible correlation to response to radiotherapy (RT) and survival was studied. A third aim of this thesis was to investigate if HPV is a potential risk factor for the increase in incidence of tonsillar cancer that has been observed in Sweden. Furthermore, presence of HPV, viral load and expression of the viral oncogenes E6 and E7 in tonsillar cancer was investigated and correlated to clinical outcome. In tongue cancer, HPV DNA detected by PCR was more commonly found in base of tongue cancer (40%) as compared to mobile tongue cancer (2.4%), and was a positive prognostic factor for survival in patients with base of tongue cancer. This finding indicates that HPV might not only be involved in tonsillar cancer, but also in base of tongue cancer, which has a similar histology and is also a part of oropharynx. In tonsillar cancer there was a strong correlation between a high expression of p16INK4a detected by immunohistochemistry (IHC) and presence of HPV detected by PCR. However, only high expression of p16INK4a, and not the presence of HPV, was shown to be a predictive factor for complete response to RT in tonsillar cancer. Nevertheless, both p16INK4a and HPV were positive predictive factors for clinical outcome. The incidence of tonsillar cancer and presence of HPV was studied in the Stockholm area during 1970-2002. HPV was detected by PCR in 49% of the patient samples and 87% of these were positive for HPV-16. The frequency of HPV positive tonsillar cancer increased 2.9-fold from 1970 to 2002 and during the same time period a parallel 2.8-fold increase in the incidence of tonsillar cancer was observed. These results strongly support HPV as a risk factor for the increase in incidence of tonsillar cancer. In the tonsillar cancer patients above, the finding of HPV as a positive prognostic factor in tonsillar cancer for clinical outcome was confirmed. In addition, HPV viral load and expression of the viral oncogenes E6 and E7 was analyzed with real time quantitative PCR and reverse transcriptase PCR in the HPV-16 positive tonsillar cancer samples. In most HPV-16 positive tumors, expression of E6 and E7 was ascertained. However, in contrast to earlier studies a high viral load was not correlated to survival. The findings of an increase in incidence of tonsillar cancer and a parallel increase in frequency of HPV positive tumors, a better disease specific survival, and the expression of viral oncogenes strongly support previous findings that HPV positive tonsillar cancer should be considered a different disease entity. If the now available prophylactic vaccines are included in the childhood vaccination program for girls, the possible effects on HPV positive tonsillar cancer should be discussed, since most patients with HPV positive tonsillar cancer are men.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet , 2008. , 49 p.
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-48260ISBN: 978-91-7357-537-9 (print)OAI: oai:DiVA.org:umu-48260DiVA: diva2:447688
Public defence
2008-03-28, Cancercentrum Karolinska R8:00, Karolinska universitetssjukhuset Solna, Stockholm, 09:00 (English)
Opponent
Supervisors
Available from: 2011-11-10 Created: 2011-10-13 Last updated: 2011-11-10Bibliographically approved
List of papers
1. Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients.
Open this publication in new window or tab >>Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients.
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2004 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 112, no 6, 1015-9 p.Article in journal (Refereed) Published
Abstract [en]

The frequency of human papilloma virus (HPV) and its influence on clinical outcome was analyzed retrospectively in pre-treatment paraffin embedded biopsies from 110 patients with tongue cancer. The presence of HPV DNA was examined in 85 mobile tongue tumors and 25 base of tongue tumors by a polymerase chain reaction (PCR) with 2 general primer pairs, GP5+/6+ and CPI/IIG. When HPV-DNA was found, HPV-type specific primers and direct sequencing were used for HPV sub-type verification. Twelve of 110 (10.9%) samples were HPV-positive; 9 for HPV-16, 1 for HPV-33, 1 for HPV-35 and 1 could not be analyzed because of shortage of DNA. HPV was significantly more common in base of tongue tumors (10/25, 40.0%) compared to tumors of the mobile tongue (2/85, 2.3%). The influence of HPV on clinical outcome in mobile tongue cancer could not be studied, due to that HPV was present in too few cases. Of the 19 patients with base of tongue cancer that were included in the survival analysis, however, 7 patients with HPV-positive base of tongue cancer had a significantly favorable 5-year survival rate compared to the 12 HPV-negative patients. In conclusion, HPV is significantly more common in base of tongue cancer than in mobile tongue cancer, and has a positive impact on disease-specific survival in patients with base of tongue cancer.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-48182 (URN)10.1002/ijc.20490 (DOI)15386365 (PubMedID)
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2017-12-08Bibliographically approved
2. P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma.
Open this publication in new window or tab >>P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma.
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2005 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, no 6C, 4375-83 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Human papillomavirus (HPV) in tonsillar carcinoma is correlated with favourable clinical outcome. Here, p16(INK4A), in situ HPV DNA hybridisation (ISH) and HPVL1 capsid detection were evaluated in tonsillar carcinoma to predict the response to radiotherapy (RT) and prognosis.

MATERIALS AND METHODS: Fifty-one pre-treatment paraffin-embedded tonsillar cancer biopsies were analysed. Immunohistochemistry (IHC) was used for p16(INK4A) and HPVL1 capsid analysis and PCR and ISH for HPV detection.

RESULTS: High-risk HPV DNA was detected by PCR in 49% of the tumours. P16(INK4a) staining was correlated to HPV In the high-grade p16(INK4a) staining group, 94% had a complete RT response. High p16(INK4a) staining as well as the HPV PCR-positive cases had a favourable prognosis. HPV DNA ISH and L1 IHC could not predict RT response or clinical outcome.

CONCLUSION: P16(INK4a) overexpression was correlated to HPV in tonsillar carcinoma and is useful for predicting RT response and prognosis in tonsillar carcinoma patients.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-48181 (URN)16334111 (PubMedID)
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2017-12-08Bibliographically approved
3. Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer.
Open this publication in new window or tab >>Human papillomavirus as a risk factor for the increase in incidence of tonsillar cancer.
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2006 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 119, no 11, 2620-2623 p.Article in journal (Refereed) Published
Abstract [en]

Smoking and alcohol are well-known etiological factors in tonsillar cancer. However, as in cervical cancer, human papillomavirus (HPV) is currently found in a sizable proportion of tonsillar cancer. Recent reports from the U.S. and Finland show an increase in the incidence of tonsillar cancer, without a parallel rise in smoking and alcohol consumption. This study investigates whether the incidence of tonsillar cancer has also changed in Sweden and whether a possible explanation of the increase is a higher proportion of HPV-positive tonsillar cancer. The incidence of tonsillar cancer between 1970 and 2002 in the Stockholm area was obtained from the Swedish Cancer Registry. In parallel, 203 pretreatment paraffin-embedded tonsillar cancer biopsies taken during 1970-2002 from patients in the Stockholm area were tested for presence of HPV DNA by PCR. The incidence of tonsillar cancer increased 2.8-fold (2.6 in men and 3.5 in women) from 1970 to 2002. During the same period, a significant increase in the proportion of HPV-positive tonsillar cancer cases was observed, as it increased 2.9-fold (p < 0.001). The distribution of HPV-positive cases was 7/30 (23.3%) in the 1970s, 12/42 (29%) in the 1980s, 48/84 (57%) in the 1990s and 32/47 (68%) during 2000-2002. We have demonstrated a highly significant and parallel increase both in the incidence of tonsillar cancer and the proportion of HPV-positive tumors. Hence, HPV may play an important role for the increased incidence of tonsillar cancer. This should definitely influence future preventive strategies as well as treatment for this type of cancer.

Keyword
human papillomavirus, tonsillar cancer, HPV-16
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-48166 (URN)10.1002/ijc.22177 (DOI)
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2017-12-08
4. Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7.
Open this publication in new window or tab >>Human papillomavirus is a favourable prognostic factor in tonsillar cancer and its oncogenic role is supported by the expression of E6 and E7.
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2007 (English)In: Molecular oncology, ISSN 1878-0261, Vol. 1, no 3, 350-5 p.Article in journal (Refereed) Published
Abstract [en]

From 1970 to 2002 in the Stockholm area, we revealed a parallel three-fold increase in the incidence of tonsillar cancer and the proportion of human papillomavirus (HPV) positive tonsillar cancer cases, indicating a possible role of HPV infection in this disease. We have now examined whether HPV and viral load in pre-treatment tonsillar cancer biopsies correlates to disease prognosis, and whether the presence of HPV-16 E6 and E7 mRNA could be ascertained. The presence of HPV-16, but not viral load, in tonsillar cancer was shown to be a favourable prognostic factor for clinical outcome. Moreover, E6 and/or E7 were expressed in almost all assessable HPV-16 positive cases, supporting an oncogenic role of HPV-16 in tonsillar cancer.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-48176 (URN)10.1016/j.molonc.2007.08.005 (DOI)19383307 (PubMedID)
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2011-11-11

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