Expression of Phosphorylated ERK in Pancreatic Endocrine Neoplasms as a Predictor of Tumor Behavior
KM Devaraj, H Remotti. Columbia University Medical Center, New York, NY
Background: Aberrant activation of the RAF/MEK/ERK MAPK pathway has been associated with a number of cancers and is thought to play an important role in tumor angiogenesis, invasion, metastasis, and chemotherapeutic drug response. Little is known about the molecular pathogenesis of pancreatic endocrine neoplasms (PEN) which comprise 8% of pancreatic tumors. PEN are generally indolent, however a subset of PEN show a more aggressive clinical behavior. Currently the most important prognostic factor in determining patient survival is the presence of metastases at the time of diagnoses. In the absence of metastases, other prognostic criteria include tumor size, vascular invasion, and mitotic rate. We investigate the immunohistochemical expression of activated (phosphorylated) ERK1/2 (pERK) in PEN to see if the MEK/ERK pathway is activated in these tumors and to determine if expression of pERK correlates with tumor behavior.
Design: Fifty-two cases of PEN resected during the interval 1998 to 2006 were retrieved from the tissue archives. Patient and tumor characteristics were recorded. Six tissue microarrays were created from paraffin-embedded blocks of PEN, sampling five 2mm cores of tumor and one 2mm core of normal pancreas for each case. Immunohistochemistry for pERK1/2 (Cell Signaling Technology, Inc) was performed on 5 micron sections of the PEN TMAs. Cytoplasmic staining intensity was graded on a scale of 1+ to 3+ and percentage of positive staining tumor cell nuclei recorded (<5% of nuclear staining considered negative).
Results: Expression of pERK was seen in 25% (13/52) PEN cases. Nuclear staining was patchy and often noted in tumors showing diffuse cytoplasmic staining. Between pERK positive and pERK negative groups there was no significant differences in patient sex, median age (61 vs. 62 yrs), or tumor size (2.5 vs. 2.0 cm). Vascular invasion was present in 85% (11/13) of pERK+ cases, compared to 46% (18/39) of pERK- cases (p=0.016). Similarly, 85% of pERK+ cases were locally invasive vs. 44% of pERK- cases (p=0.010). Lymph node metastases were noted in 46% (6/13) of pERK+ cases compared to 18% (7/39) of pERK- cases (p=0.042).
Conclusions: Expression of pERK in pancreatic endocrine neoplasms strongly correlates with markers of tumor aggressiveness and poor prognosis. These findings suggest that the MEK/ERK pathway may be important in PEN progression and metastases. Furthermore a subset of aggressive PEN with expression of pERK may benefit from treatment with multikinase inhibitors.
Category: Liver & Pancreas
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 217, Tuesday Afternoon