A comparative analysis of pancreas cyst fluid CEA and histology with DNA mutational analysis in the detection of mucin producing or malignant cysts.

CONTEXT: The main objective of pancreatic cyst fluid analysis is to differentiate mucin-producing or malignant cysts from other cysts which have a benign course. K-ras-2 point mutation and at least two mutations of allelic imbalance or loss of heterozygosity with good quality DNA has been suggested to predict mucinous cystic neoplasm (MCN). Elevated carcinogenic embryonic antigen (CEA) level in cyst fluid has also been shown to be predictive of mucinous or malignant cysts.
OBJECTIVE: Identify the clinical impact of DNA mutational analysis of pancreatic cyst fluid with its correlation to cyst fluid chemistry and histologic analysis. PATIENTS: This retrospective analysis included all consecutive patients with pancreatic cysts who presented for evaluation by endoscopic ultrasound (EUS) with fine needle aspiration (FNA) over an 18 month period until November 2007. MAIN OUTCOME MEASURES: DNA analysis performed by Pathfinder TG (RedPath Integrated Pathology, Inc., Pittsburgh, PA, USA) and fluid CEA exceeding 192 ng/dL were used to suggest mucinous or malignant cysts. These parameters were compared to surgical histology or cytopathology of FNA specimens.
RESULTS: Twenty-seven consecutive patients with cysts had samples submitted for DNA analysis which included 15 men and 12 women (mean age 62.8 and 61.3 years, respectively). In 20 patients, all parameters including cyst fluid, DNA analysis, and histology were available for comparison. Consistent findings were seen in 7/20 (35%) in which all parameters suggested negative benign findings. CEA level was elevated in 7 patients of which 4 had mucinous or malignant histology. In the remaining 13 patients with low CEA levels, 11 had negative histology. The sensitivity and specificity of CEA based on these results was 66% and 78.6% respectively. The positive predictive value (PPV) of CEA was 57% and the negative predictive value (NPV) was 84.6%. K-ras-2 mutation was detected in 3 patients, absent in 17 patients and falsely negative in 4 cases based on histology. The sensitivity and specificity were 33% and 92.6% respectively. The PPV was 66% and NPV was 76%. Detection of loss of heterozygosity mutations was noted in 7 patients, of which 4 were falsely positive. In the remaining 13 patients, 3 were falsely negative. The sensitivity and specificity were 50% and 71% respectively. The PPV was 42.9% and NPV was 76.9%. In a group of 6 patients with available surgical histology demonstrating mucin-producing or malignant cysts, fluid CEA level had a sensitivity of 66.7%. However, K-ras-2 and loss of heterozygosity mutational analysis had a much lower sensitivity at 33% and 50% respectively.
CONCLUSIONS: Consistency in histology, CEA levels, and K-ras-2 and loss of heterozygosity mutations was seen in only 35% of cases, all of which were benign cysts. In the detection of malignant cysts, elevated CEA levels were more predictive of histology in comparison to K-ras-2 or loss of heterozygosity mutations. Additionally, false positivity of loss of heterozygosity mutations was noted to be considerably higher than K-ras-2 mutations or even fluid CEA levels. These findings suggest that DNA mutation analysis should not be used routinely but rather selectively in the evaluation of pancreatic cysts.