An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.
BACKGROUND
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs.


METHODS
Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1-5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan-Meier and Cox regression methods.


RESULTS
Eighty-six consecutive cases were included: 51% male, median age 51 (range 16-82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006).


CONCLUSIONS
We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up.
Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK.
D J
DJ
Pinato
Department of Endocrinology, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS London, UK.
T M
TM
Tan
Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK.
S T K
ST
Toussi
Department of Endocrinology, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS London, UK.
R
R
Ramachandran
Department of Endocrinology, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS London, UK.
N
N
Martin
Department of Endocrinology, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS London, UK.
K
K
Meeran
Department of Pathology, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS London, UK.
N
N
Ngo
Department of Pathology, Imperial College London, Hammersmith Campus, Du Cane Road, W120HS London, UK.
R
R
Dina
Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, W120HS London, UK.
R
R
Sharma
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000098:blood supply* / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D010641:Phenotype; D017481:Receptors, Somatostatin / Q000096:biosynthesis; D015996:Survival Rate; D046888:Tissue Array Analysis; D055815:Young Adult
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017481:Receptors, Somatostatin; C574734:SSTR2 protein, human