Background: Detection of bone marrow micrometastases (BMMs) predicts poor prognosis in epithelial malignancy. Angiogenesis is essential for tumour growth and dissemination. VEGF is an angiogenic cytokine that can be detected in serum or plasma (S-VEGF, P-VEGF) of cancer patients. We aim to establish if patients with resectable gastroesophageal cancer who have BMMs, display differences in Circulating VEGF over those that do not.
Methods: S-VEGF and P-VEGF was measured in 43 patients undergoing gastroesophageal cancer resection using an ELISA specific for Human VEGF (R&D Systems, Minneapolis, MN). A single bone marrow aspirate was taken from the iliac crest pre-operatively. Following cytospin preparation, slides were stained with anti-cytokeratin antibodies, CAM 5.2 (BDIS, San Jose, CA) and AE1/3 (Dako, Carpenteria, CA). Micrometastatic cells were identified using light microscopy and confirmed morphologically. Standard pathological analysis was undertaken on resected specimens.
Results: VEGF data expressed as median (IQR) is summarized in the table below. Statistical analysis is by Mann Whitney U and Fisher s Exact Tests. BMMs were detected in 19/43 cases (44%). The majority of cells detected were single cells, though occasional clumps were seen. BMMs were significantly associated with advanced T stage (p=0.009), circumferential margin involvement (p=0.001) and detection of lymphovascular invasion (p=0.012). Multivariate analysis incorporating the above factors, along with lymph node involvement and combined pathological stage, revealed that only circumferential margin involvement and P-VEGF were independent predictors of detecting micrometastatic cells in the bone marrow (p=0.014 and p=0.042, respectively).
Conclusions: These findings support the hypothesis that P-VEGF might reflect a measure of the angiogenic status of the primary tumor and thus the propensity for systemic dissemination.
Circulating VEGF and BMM status
BMM positive (n=19) BMM negative (n=24)
P-VEGF (pg/mL) *20 (12-47) 10 (0-21)
S- VEGF (pg/mL) 277 (180-489) 260 (126-341)
*p=0.022 versus BMM Negative
