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Stage T1 Urinary Bladder Carcinoma: Investigation of A Population-Based Cohort
Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Approximately 2 300 new cases of urinary bladder carcinoma (UBC) are diagnosed every year in Sweden. This type of cancer is characterized as a long-standing disease with a high risk of recurrence and progression from an indolent to a more aggressive course. UBC occurs in a non-muscle-invasive form (stages Ta and T1), which is treated mainly with local resection and BCG instillation, and a muscle-invasive form (stage ≥ T2), for which the treatment of choice is irradiation or cystectomy.

The aim of the research underlying this thesis was to explore the factors involved in tumor development and progression, and to find prognostic markers for recurrence and progression in patients with primary stage T1 urothelial carcinoma of the bladder (UCB).

Tumor tissue in archived paraffin blocks from patients diagnosed with that type of malignancy was used in the four studies that were conducted. This was a population-based project, because all of the patients had been reported to the cancer center in the Southeast Healthcare Region in Sweden from 1992 to 2001. The follow-up time was comparable long in the cases included and was intended to be at least 10 years.

The hospital records were reviewed to gather information on clinical characteristics of the tumors, such as size and multiplicity, as well as treatment modalities, recurrence and/or progression, and eventual death from UBC. The original tumor slides were re-evaluated. These two initial activities yielded a study population comprising 211 well-characterized patients with primary T1 UCB. Some of the originally selected patients were excluded due to missing paraffin blocks or poor quality of the tumor material, the latter being particularly important in the genetic analyses conducted in the fourth study.

Ordinary light microscopy was performed to evaluate specific tumor characteristics, such as lymphovascular tumor infiltration, and for T1 sub-staging. Immunohistochemistry was carried out to, among other things, analyze cell cycle regulators. Furthermore, pyrosequencing, single-strand conformation analysis (SSCA), and Sanger sequencing were conducted in the fourth study to assess mutations in the p53 gene and murine double minute 2 SNP309 promoter polymorphism. Statistical analyses to estimate the risk of tumor recurrence and progression were carried out in all four investigations.

Conclusions: This population-based cohort of patients with well-characterized T1 tumors of the urinary bladder showed high rates of recurrence (80%) and progression (39%), and the aggressiveness is underlined by the fact that 32% died from the disease. Lymphovascular tumor infiltration and abnormal immunohistochemical staining for p16 were found to be associated with tumor progression, and in the future analysis of these parameters might be used in treatment decisions regarding T1 bladder tumors. No other clinical or pathological variable or cell cycle regulator was associated with progression, and none of the genetic analyses conducted in the current studies were helpful in predicting outcome or explaining the mechanisms of tumor development.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 79 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1335
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-85017ISBN: 978-91-7519-779-1 (print)OAI: oai:DiVA.org:liu-85017DiVA: diva2:563594
Public defence
2012-11-29, Nils-Holger salen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2012-10-31Bibliographically approved
List of papers
1. HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder
Open this publication in new window or tab >>HER2 status in primary stage T1 urothelial cell carcinoma of the urinary bladder
2012 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 2, 102-107 p.Article in journal (Refereed) Published
Abstract [en]

Objective. The HER2 receptor is involved in pathways essential for cell proliferation, and is an important predictive and prognostic factor in breast cancer. HER2 probably plays a critical role in many types of cancer, including urothelial carcinoma of the bladder (UCB). Stage T1 UCB exhibits heterogeneous clinical behaviour, and the frequency of HER2 expression in such disease has not been thoroughly examined. The aim of this study was to use an immunohistochemical technique to evaluate the frequency of HER2 expression in a defined population-based cohort of patients registered as having primary stage T1 UCB. Material and methods. The initial study population comprised 285 patients registered as having primary stage T1 UCB. The original histological specimens were re-evaluated with regard to T stage and World Health Organization grade. Hospital records provided information on tumour size, multiplicity, possible presence of histologically proven recurrence and progression. The patients were followed for at least 5 years or until death. In tumours still considered stage T1 after re-evaluation, HER2 was investigated by immunohistochemistry of paraffin-embedded material and scored according to the guidelines used in breast cancer. Results. After histopathological re-evaluation, 201 patients were still T1 UCB and could be investigated regarding HER2 expression. HER2 overexpression was observed in 25 of those patients (12.4%). HER2 status was not significantly associated with recurrence or progression. Conclusions. HER2 was overexpressed in 12.4% of the present cohort of patients with primary stage T1 UCB. There was no significant association between tumour HER2 status and prognosis.

Place, publisher, year, edition, pages
Informa Healthcare, 2012
Keyword
HER2 overexpression, stage T1, urinary bladder carcinoma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76526 (URN)10.3109/00365599.2011.637955 (DOI)000301539200005 ()
Available from: 2012-04-12 Created: 2012-04-11 Last updated: 2017-12-07
2. Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours
Open this publication in new window or tab >>Population-based study on prognostic factors for recurrence and progression in primary stage T1 bladder tumours
2013 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 47, no 3, 188-195 p.Article in journal (Refereed) Published
Abstract [en]

Objective. Stage T1 urothelial carcinoma of the bladder (UCB) exhibits heterogeneous clinical behaviour, and the treatment is controversial. The aim of this study was to evaluate prognostic factors for UCB in a defined, population-based cohort comprising patients with a first time diagnosis of primary stage T1 UCB.

Material and methods. The study population initially consisted of 285 patients with primary stage T1 UCB reported to the regional Bladder Cancer Registry in the Southeast Healthcare Region of Sweden from 1992 to 2001. The histological specimens were re-evaluated concerning stage, substaging of T1, World Health Organization (WHO) grade, lymphovascular invasion (LVI), tumour volume and total resected volume. Hospital records provided data on tumour size and multiplicity, occurrence of possible relapse and/or progression, death from UCB and whether treatment was given.

Results. After re-evaluation, the study population comprised 211 patients. The median follow-up time was 60 months. LVI was a prognostic factor for UCB progression and recurrence. Tumour size larger than 30 mm and multiplicity increased the risk of recurrence. T1 substaging, tumour volume and total resected volume were not associated with recurrence or tumour progression.

Conclusions. LVI is significantly correlated with progression and recurrence in patients with primary stage T1 UCB. Therefore, the presence of LVI should be evaluated in every new case of T1 UCB.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85012 (URN)10.3109/00365599.2012.719539 (DOI)000321415400004 ()
Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
3. Immunohistochemical Evaluation of Cell Cycle Regulators: Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer
Open this publication in new window or tab >>Immunohistochemical Evaluation of Cell Cycle Regulators: Impact on Predicting Prognosis in Stage T1 Urinary Bladder Cancer
Show others...
2012 (English)In: ISRN Urology, ISSN 2090-5807, E-ISSN 2090-5815, Vol. 2012, 379081Article in journal (Other academic) Published
Abstract [en]

Background and Objective. The cell cycle is regulated by proteins at different checkpoints, and dysregulation of this cycle plays a role in carcinogenesis. Matrix metalloproteinases (MMPs) are enzymes that degrade collagen and promote tumour infiltration. The aim of this study was to evaluate the expression of various cell cycle regulators and MMPs, and to correlate such expression with progression and recurrence in patients with stage T1 urothelial carcinoma of the bladder (UCB).

Patients and Methods. This population-based cohort study comprised 201 well-characterized patients with primary stage T1 urothelial carcinoma of the bladder. Immunohistochemistry was performed on formalin-fixed material to quantify expression of cell cycle regulators and two MMPs.

Results. Normal expression of p53 and abnormal expression of MMP9 were associated with greater risk of tumour recurrence. Also, normal p16 expression was related to a lower risk of tumour progression. MMP2, p21, cyclin D1, and pRb showed no significant results that could estimate progression or recurrence.

Conclusions. Normal p16 expression is associated with a lower risk of tumour progression, but immunohistochemistry on cell cycle regulators and MMPs has little value in predicting the prognosis in stage T1 UCB.

Place, publisher, year, edition, pages
Hindawi Publishing Corporation, 2012
Keyword
Urinary bladder cancer, immunohistochemistry, prognostic factors, cell cycle regulators
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:liu:diva-85013 (URN)10.5402/2012/379081 (DOI)
Note

On the day of the defence day the status of this article was:

Manuscript

Available from: 2012-10-30 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved
4. MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1
Open this publication in new window or tab >>MDM2 SNP309 promoter polymorphism and p53 mutations in urinary bladder carcinoma stage T1
Show others...
2013 (English)In: BMC Urology, ISSN 1471-2490, E-ISSN 1471-2490, Vol. 13, no 5Article in journal (Refereed) Published
Abstract [en]

Background: Urinary bladder carcinoma stage T1 is an unpredictable disease that in some cases has a good prognosis with only local or no recurrence, but in others can appear as a more aggressive tumor with progression to more advanced stages. The aim here was to investigate stage T1 tumors regarding MDM2 promoter SNP309 polymorphism, mutations in the p53 gene, and expression of p53 and p16 measured by immunohistochemistry, and subsequently relate these changes to tumor recurrence and progression. We examined a cohort of patients with primary stage T1 urothelial carcinoma of the bladder and their tumors.

Methods: After re-evaluation of the original slides and exclusions, the study population comprised 141 patients, all with primary stage T1 urothelial carcinoma of the bladder. The hospital records were screened for clinical parameters and information concerning presence of histologically proven recurrence and progression. The paraffin-embedded tumor material was evaluated by immunohistochemistry. Any mutations found in the p53 gene were studied by single-strand conformation analysis and Sanger sequencing. The MDM2 SNP309 polymorphism was investigated by pyrosequencing. Multivariate analyses concerning association with prognosis were performed, and Kaplan-Meier analysis was conducted for a combination of changes and time to progression.

Results: Of the 141 patients, 82 had at least one MDM2 SNP309 G allele, and 53 had a mutation in the p53 gene, but neither of those anomalies was associated with a worse prognosis. A mutation in the p53 gene was associated with immunohistochemically visualized p53 protein expression at a cut-off value of 50%. In the group with p53 mutation Kaplan-Meier analysis showed higher rate of progression and shorter time to progression in patients with immunohistochemically abnormal p16 expression compared to them with normal p16 expression (p = 0.038).

Conclusions: MDM2 SNP309 promoter polymorphism and mutations in p53 were not associated with worse prognosis in this cohort of patients with primary stage T1 urinary bladder carcinoma. However, patients with abnormal p16 expression and a mutated p53 gene had a higher rate of and a shorter time to progression, and p53 gene mutation was associated with an abnormal immunohistochemistry for p53 at a cut-off of 50%.

Place, publisher, year, edition, pages
BioMed Central, 2013
Keyword
Urinary bladder cancer, immunohistochemistry, prognostic factors, cell cycle regulators
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85016 (URN)10.1186/1471-2490-13-5 (DOI)000314924600001 ()
Available from: 2013-04-02 Created: 2012-10-30 Last updated: 2017-12-07Bibliographically approved

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