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Prognostic Relevance of Survivin in Pancreatic Endocrine Tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Endokrin tumörbiologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Endokrin tumörbiologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. (Endokrin tumörbiologi)
2012 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 6, 1411-1418 p.Article in journal (Refereed) Published
Abstract [en]


Better prognostic markers are needed for pancreatic endocrine tumors. Survivin is an apoptosis inhibitor that is suggested to have a negative prognostic impact in several tumor types. Contradictory data exist, especially regarding the significance of a nuclear versus cytoplasmic location of survivin. The prognostic relevance of nuclear and cytoplasmic survivin expression in pancreatic endocrine tumors-controlled for the tumor Ki-67 index, World Health Organization classification, and TNM stage-was investigated.


A total of 111 patients treated at a tertiary referral center were retrospectively evaluated. Clinical data were gathered from medical records. Immunohistochemistry for survivin and Ki-67 was performed on paraffin-embedded tissue. Univariate and multivariate Cox analyses were performed.


Patients with tumors that had <5% survivin-positive nuclei had a mean survival of 225 months [95% confidence interval (CI) 168-281]. The corresponding figure for patients with 5 to 50% survivin-positive tumor cell nuclei was 101 months [95% CI 61-140; hazard ratio (HR) 2.4; P < 0.01) and with >50% survivin-positive nuclei 47 months (95% CI 24-71; HR 4.9; P < 0.001). Nuclear survivin expression in >50% of the tumor cells was an independent marker of a poor prognosis (HR 5.7; P < 0.01). Cytoplasmic survivin was not a significant prognostic factor in the multivariate analysis (HR 0.94; P = 0.90).


High expression of nuclear survivin is a significant marker of a poor prognosis in patients with a pancreatic endocrine tumor.

Place, publisher, year, edition, pages
2012. Vol. 36, no 6, 1411-1418 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-162584DOI: 10.1007/s00268-011-1345-7ISI: 000304096800030PubMedID: 22089920OAI: oai:DiVA.org:uu-162584DiVA: diva2:460958
Available from: 2011-12-01 Created: 2011-12-01 Last updated: 2013-01-22Bibliographically approved
In thesis
1. The MEN 1 Pancreas: Tumor Development and Haploinsufficiency
Open this publication in new window or tab >>The MEN 1 Pancreas: Tumor Development and Haploinsufficiency
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Multiple Endocrine Neoplasia Type I Syndrome (MEN 1) is a monogenic autosomal dominantly inherited cancer syndrome caused by a heterozygous loss of the MEN1 gene, predisposing for endocrine cell proliferation and tumor formation. MEN 1 carriers classically develop tumors in endocrine organs; the parathyroids, the endocrine pancreas, and the pituitary. Other organs, endocrine and non-endocrine, may also be affected. The most common cause of death in MEN 1 is pancreatic endocrine tumor (PNET), which exhibit inactivation of both MEN1 alleles. The increased proliferation prior to loss of the wild-type allele indicates haploinsufficiency, and little is known concerning the mechanisms behind MEN 1 PNET development. The MEN1 protein, menin, lacking homology with other known proteins, is involved in several aspects of transcriptional regulation and chromatin organization.

We report differential expression and subcellular localization of transcription factors important in pancreatic development, in human and mouse MEN 1 pancreas, compared to non-MEN 1 pancreas. A predominantly cytoplasmic localization of Neurogenin3 and NeuroD1 was observed in tumors as well as in MEN 1 non-tumorous pancreas.

Notch signaling factor expression and localization were examined in the pancreas of a heterozygous Men1 mouse model, and compared with that of wild-type littermates. Nuclear Hes1 was lost in tumors, concomitant to weaker Notch1 NICD expression, and further, analyzed using qPCR, it was shown that Notch1 was less expressed in heterozygous islets compared to wild-type islets.

Performing a global gene expression array, we identified differential gene expression in five-week-old heterozygous Men1 mouse islets, compared to islets from wild-type littermates. The array results for a subset of the differentially regulated genes were corroborated using qPCR, western blotting and in situ PLA. We additionally observed significantly accelerated proliferation in islets from young heterozygous animals.

It is often problematic to determine prognosis for individual patients with PNET. This is especially true in the group of patients with well differentiated endocrine carcinomas. In the absence of metastases, morphological signs of malignancy are frequently lacking. We evaluated the expression of nuclear and cytoplasmic survivin in a clinically characterized patient material (n=111), and a high nuclear survivin expression proved to be a significant negative prognostic factor for survival.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 69 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 792
MEN 1, PNET, tumor development, haploinsufficiency, survivin
National Category
Cancer and Oncology Endocrinology and Diabetes
Research subject
Endocrinology and Diabetology
urn:nbn:se:uu:diva-175033 (URN)978-91-554-8415-6 (ISBN)
Public defence
2012-09-28, Enghoffsalen, Ingång 50, Akademiska Sjukhuset, UPPSALA, 13:15 (English)
Available from: 2012-08-31 Created: 2012-05-31 Last updated: 2013-01-22Bibliographically approved

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Halin Lejonklou, MargaretaStålberg, PeterSkogseid, Britt
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