Abstract
Neuroendocrine tumors (NET) are heterogeneous tumors with widely variable survival. It is unknown whether they express EpCAM (epithelial cell adhesion molecule) and thus whether NET circulating tumor cells (CTC) are detectable. We systematically investigated EpCAM expression and CTC detection in patients with metastatic NETs and evaluated the potential of CTCs to predict radiological progression. EpCAM protein expression was evaluated in 74 samples of formalin-fixed, paraffin-embedded NET tissue by immunohistochemistry. Seventy-nine patients with metastatic NETs (42 midgut, 5 unknown primary, 19 pancreatic, 13 bronchopulmonary) had blood samples drawn for CTC isolation and enumeration utilizing the CellSearch platform. Patients were classified as having progressive or nonprogressive disease on the basis of serial imaging. Strong homogeneous, membranous EpCAM expression was observed in all ileal (n = 26) and pancreatic NETs (n = 16), whereas variable EpCAM expression was observed in bronchopulmonary NETs (n = 13). Forty-three percent of midgut and 21% of pancreatic NETs had CTCs detected with a range of 0-62 and 0-11, respectively. The absence of CTCs was strongly associated with stable disease (P < 0.001). There was a moderate correlation between CTC levels and urinary 5-hydroxyindole acetic acid (r = 0.5, P = 0.007) and between CTC levels and burden of liver metastases (B = 8.91, P < 0.001). There was no or low correlation between CTC levels and Ki-67 (r = 0.08, P = 0.59) and serum chromogranin A (r = 0.246, P = 0.03). This is the first systematic analysis showing EpCAM expression and CTC detection in NETs. CTCs seem to be associated with progressive disease and may provide useful prognostic information given the variable survival rates in these tumors.
Highlights
Neuroendocrine tumors (NET) are a rare, heterogeneous group of tumors arising most commonly from the gastrointestinal tract, pancreas, and lungs
Forty-three percent of midgut and 21% of pancreatic NETs had circulating tumor cells (CTC) detected with a range of 0– 62 and 0–11, respectively
There was a moderate correlation between CTC levels and urinary 5-hydroxyindole acetic acid (r 1⁄4 0.5, P 1⁄4 0.007) and between CTC levels and burden of liver metastases (B 1⁄4 8.91, P < 0.001)
Summary
Neuroendocrine tumors (NET) are a rare, heterogeneous group of tumors arising most commonly from the gastrointestinal tract, pancreas, and lungs. Their natural history is variable, with median survival ranging from approximately 6 months in aggressive high-grade tumors to up to 20 years in more indolent disease [1]. Current methods of monitoring progression in NETs and response to treatment include serial imaging over many years. It has been suggested that CTC detection can aid appropriate patient stratification and design of tailored treatments, which are the aims of ongoing studies (such as SWOG S0500)
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