MD Thesis

‘Doctor of Medicine’ Thesis

The University of Manchester Abstract of Thesis

Submitted by Ewen A. Griffiths for the Degree of Doctor of Medicine and entitled ‘Assessment of hypoxia associated markers in oesophagogastric cancer’ July 2006.

Introduction

There is a need to increase understanding of oesophagogastric cancer biology and develop methods for determining prognosis. Hypoxia is implicated in the aetiology and prognosis of a number of cancers, but has not been studied in oesophagogastric cancer. It is important to understand the patient and tumour characteristics that might influence biological data. For example, tumour length and circumferential resection margin (CRM) status have not been adequately assessed as prognostic markers in oesophageal cancer.

Aims

1) To investigate the relationship of tumour length and CRM with other histopathological variables and survival in patients with surgically treated oesophageal cancer. 2) To establish a retrospective database of patients with gastric and gastrooesophageal junctional (GOJ) cancer; analyse relevant clinico-pathological prognostic factors prior to molecular marker analysis. 3) To investigate HIF-1α and HIF-2α expression as prognostic markers in gastric and GOJ cancer. 4) To investigate HIF-1α and other related markers (HIF-2α, Epo, Epo-R, Glut-1, Ki67, VEGF) in oesophageal and gastric adenocarcinoma carcinogenesis. 5) To establish a prospective study to measure tumour hypoxia (by pimonidazole staining).

Findings

1) Both tumour length and CRM status were independent prognostic factors in surgically treated patients with oesophageal cancer. 2) A retrospective database of 251 patients was established. Only additional surgical resection of the spleen or pancreas and ASA grade were independent predictors of prognosis. 3) In 177 patients for whom tissue was obtained, HIF-1α expression had no prognostic significance. However, HIF-1α expression pattern was a significant predictor of survival on univariate analysis; patients with HIF-1α expression at the invasive edge had a median survival of only 18 mths compared with 33 mths in HIF-1α negative tumours. HIF-2α expression was a prognostic factor on univariate analysis. Neither HIF-1α nor HIF-2α had independent prognostic significance. 4) The expression of the hypoxia associated markers increased significantly from normal tissue to invasive malignancy in both the oesophageal and gastric carcinogenesis models. 5) A prospective study was established after LREC and R&D approval was obtained. Data for the first 9 patients enrolled showed intra and inter-tumoral variation in hypoxia.

Conclusions

1) The development of imaging approaches for assessing tumour length pre-operatively would be of value. CRM should continue to be reported on routine histopathology. 2) There are clinico-pathological and prognostic differences between GOJ and other gastric tumours. A standard classification of GOJ tumours should be adopted internationally. 3) The dependence of HIF-1α as a prognostic factor on staining pattern may be due to its differential regulation of down-stream molecules. As neither HIF-1α or HIF-2α had independent prognostic significance, they are unlikely to play a role as single markers of prognosis. The high expression of HIF-2α suggests its further study as a therapeutic target would be of value. 4) HIF-2α should be assessed as a predictive marker of disease progression in patients with Barrett’s dysplasia. 5) Some oesophagogastric cancers are strongly hypoxic