According to the American Cancer Society, 43,140 new cases and 36,800 deaths from pancreatic cancer were expected in 2010. The incidence of pancreatic adenocarcinoma in the United States decreased by 19% in males and 5% in females from 2002 to 2005 compared with the incidence in the period between 1977 and 1981. Interestingly, the incidence of pancreatic endocrine neoplasms increased over the same time periods by 106% in men and 125% in women. The 5-year survival rate for pancreatic cancer is 5%, which is the lowest among gastrointestinal malignancies. Recently, it was suggested that endoscopic ultrasound (EUS) evaluation of pancreatic cancer was an independent predictor of survival improvement in patients with locoregional pancreatic cancer. In this article, we focus on the role of EUS in the evaluation and management of pancreatic cancer, including updates on novel approaches using EUS in the regional treatment of pancreatic cancer.
The Role of EUS in Diagnosis of Pancreatic Cancer
EUS has an integral role in the diagnosis of pancreatic cancer given its high sensitivity for detecting pancreatic neoplasms and the access it affords to perform fine needle aspiration (FNA) of the suspected lesions. The sensitivity of EUS for detecting pancreatic lesions ranges from 85% to 99% in most published series. The sensitivity and accuracy of EUS are slightly higher than the sensitivity and accuracy of computed tomography (CT) in detecting small pancreatic lesions. Magnetic resonance imaging (MRI) has similar accuracy to CT scanning in detecting pancreatic cancer and vascular invasion.
Pancreatic lesions usually appear on EUS as hypoechoic lesions with an irregular border. TNM staging of pancreatic tumors by EUS is feasible and accurate. If the tumor is limited to the pancreas, it is either a T1 or T2 lesion. Lesions smaller than 2 cm are T1; lesions larger than 2 cm are T2. If the tumor extends beyond the pancreas, then it is either a T3 or T4 lesion. Tumors extending to the celiac artery or superior mesenteric artery are considered T4 lesions, whereas tumors involving any of the surrounding structures of the pancreas, such as the portal vein, duodenum, or ampulla of Vater, without involvement of the celiac artery or superior mesenteric artery are classified as T3 tumors. The distinction of a T3 from a T4 tumor is important given that tumors extending to the celiac or superior mesenteric arteries (T4) are generally not surgically resectable for cure. If malignant lymph nodes are seen around the pancreas, such as the peripancreatic, celiac, or gastrohepatic lymph nodes, then the lesion is an N1 lesion. Occasionally, distant metastasis can be seen by EUS and, in this case, the lesion is an M1 lesion, which is also inoperable. Soriano and colleageus compared the accuracy of CT, MRI, and EUS in assessing TNM staging of pancreatic cancer using surgical diagnosis as the gold standard. CT had the highest accuracy for T-staging at 74%; MRI accuracy was 68% and EUS, 62%. However, EUS had the highest accuracy for N-staging (65%) with accuracy of CT and MRI for assessing N-staging at 62% and 61%, respectively. In a prospective study by Soriano and colleagues, CT had the greatest accuracy in detecting vascular invasion (83%) in comparison with EUS and MRI. Similar results were seen in another trial by Tian and co-workers, in which they found that helical CT had the highest accuracy in detecting vascular invasion of pancreatic cancer, and EUS had the highest accuracy of assessing lymph node metastases. It is worth stressing that, although CT is more accurate in assessing T-staging of pancreatic cancer, EUS is still more sensitive and accurate in pancreatic lesions less than 3 cm in size.
FNA can be done with a variety of dedicated needles, most typically 22 gauge. Other needles available are the 25-gauge, 19-gauge, and core biopsy needles. The number of passes needed to obtain sufficient tissue for diagnosis is higher in pancreatic cancer than in other lesions, and varies from 4 to 7 passes among the studies. Combining cytologic and histologic analyses of the specimen can decrease the number of passes to 2. There is a growing body of evidence that the 25-gauge needle may be superior to the 22-gauge needle in the diagnosis of pancreatic cancer. Perhaps this is because less blood is aspirated with the 25-gauge needle, improving the cytologic assessment of the specimen. In addition, the 25-gauge needle is easier to use in areas with tough angulation, as in the case of lesions sampled from a duodenal sweep. On-site cytologic interpretation has been shown in many studies to improve yield and reduce the number of passes needed.
Limitations of EUS
Gastroenterologists should be aware of clinical scenarios in which pancreatic cancer can be missed or difficult to assess by EUS examinations. Varadarajulu and assocaites, in a prospective study of 282 patients with pancreatic masses, found that the sensitivity of EUS-FNA in detecting pancreatic cancer in the setting of chronic pancreatic was 73% compared with 91% in patients without chronic pancreatitis. In another trial by Fritscher-Ravens and colleagues, the sensitivity of EUS-FNA in detecting pancreatic cancer in patients with chronic pancreatitis was 54%, compared with 85% in patients without chronic pancreatitis. The No Endosonographic Detection of Tumor (NEST) study evaluated 20 pancreatic cancers missed by 9 experienced endosonographers. Twelve patients (60%) had chronic pancreatitis, 3 patients (15%) had a diffusely infiltrating tumor, 2 patients (10%) had a prominent ventral portion of the pancreas, and 1 patient had a recent episode of chronic pancreatitis. On the other hand, false-positive results of EUS occur in 1% of the patients. Most of these patients have chronic pancreatitis on a surgical specimen as well. Other limitations of EUS-FNA are related to the quality of specimen collected by FNA. Tumor necrosis or excessive blood on the specimen can obscure the diagnosis of pancreatic cancer. The cytopathologist’s experience and the manner in which the specimens are handled can affect the overall accuracy of EUS-FNA in detection of pancreatic cancer.
Limitations of EUS
Gastroenterologists should be aware of clinical scenarios in which pancreatic cancer can be missed or difficult to assess by EUS examinations. Varadarajulu and assocaites, in a prospective study of 282 patients with pancreatic masses, found that the sensitivity of EUS-FNA in detecting pancreatic cancer in the setting of chronic pancreatic was 73% compared with 91% in patients without chronic pancreatitis. In another trial by Fritscher-Ravens and colleagues, the sensitivity of EUS-FNA in detecting pancreatic cancer in patients with chronic pancreatitis was 54%, compared with 85% in patients without chronic pancreatitis. The No Endosonographic Detection of Tumor (NEST) study evaluated 20 pancreatic cancers missed by 9 experienced endosonographers. Twelve patients (60%) had chronic pancreatitis, 3 patients (15%) had a diffusely infiltrating tumor, 2 patients (10%) had a prominent ventral portion of the pancreas, and 1 patient had a recent episode of chronic pancreatitis. On the other hand, false-positive results of EUS occur in 1% of the patients. Most of these patients have chronic pancreatitis on a surgical specimen as well. Other limitations of EUS-FNA are related to the quality of specimen collected by FNA. Tumor necrosis or excessive blood on the specimen can obscure the diagnosis of pancreatic cancer. The cytopathologist’s experience and the manner in which the specimens are handled can affect the overall accuracy of EUS-FNA in detection of pancreatic cancer.
Newer EUS Technologies for the Detection of Pancreatic Cancer
Newer technologies have emerged to improve the diagnostic accuracy of EUS, especially in the setting of chronic pancreatitis or in other situations in which cytology results are borderline or inconclusive. In this part of the review, we discuss the role of EUS elastography, contrast-enhanced EUS, and other new technology designed to improve the diagnostic accuracy of EUS.
EUS Elastography
EUS elastography is based on the premise that the compression of tissue produces a smaller strain (displacement) in hard tissue than it does in soft tissue. Measuring this strain during EUS might aid in differentiating tissues with different strains, as in the case of chronic pancreatitis and pancreatic cancer. First-generation elastography used a qualitative method that entailed coloring tissues with different strains in different colors, in which blue represents the hardest tissue and red represented the softest tissue. The second generation of EUS elastography enabled quantitative measurement of the tissue strain thorough software programs. It is worth mentioning that real-time EUS elastography is only available in the Pentax echoendoscopes system (Pentax Medical Company, Montvale, NJ).
In the last 4 years, a stream of studies evaluating the efficacy of EUS elastrography have been published. Saftoiu and associates evaluated 43 patients with either chronic pancreatitis or pancreatic cancer who were assessed with real-time EUS elastography. The diagnostic accuracy of EUS to differentiate benign from malignant lesions was 89.7%. Although the results were promising, there was no gold standard surgical diagnosis in the series. Iglesias-Garcia and colleagues published their experience with EUS elastography in 2009. The authors evaluated 130 patients with solid pancreatic masses. The sensitivity, specificity, and diagnostic accuracy of EUS elastography for differentiating benign from malignant pancreatic lesions was 100%, 85.5%, and 94%, respectively. These studies and others used the first-generation elastography, which showed promising results in improving the sensitivity and specificity of EUS in differentiating solid pancreatic masses. However, first-generation elastography was criticized for its subjective nature; color interpretation of the tissue strain pattern was operator dependent.
The development of second-generation EUS elastography minimized this pitfall by quantitatively measuring the tissue strain. Iglesias-Garcia and co-workers evaluated the usefulness of quantitative EUS elastography in 86 patients with solid pancreatic masses. The sensitivity, specificity, and diagnostic accuracy of quantitative EUS elastography was higher than first-generation EUS elastography with values of 100%, 96.3%, and 98.7%, respectively. Shrader and associates reached 100% sensitivity and specificity in differentiating benign from malignant lesions in tissues with blue color (hard tissue), as it appears on EUS elastography histogram. However, they could not reach the same results when evaluating areas with red or green colors, which represent softer tissue. Although quantitative EUS elastography minimized the bias of qualitative evaluation, it is still unclear if it has a role in minimizing the bias of calculating the strain of the normal surrounding tissue around the lesion. In addition, further research is needed to develop pressure gauges so that the amount of the pressure applied by the echoendoscope in producing the tissue strain can be controlled.
Contrast-Enhanced EUS
Contrast-enhanced (CE)-EUS utilizes the injection of a contrast agent through the blood stream. The contrast agent contains microbubbles that can be detected by EUS in the small, low-velocity vasculature of pancreatic tumors. Unlike the contrast agents used in CT or MRI, ultrasound contrast agents are confined to the blood stream and do not diffuse to the extracellular space. The contrast agent is injected during the EUS examination and allows for real-time evaluation of the area of interest. The use of harmonic EUS can enhance the ability to detect the contrast agent in the microvasculature of the pancreatic tumor. So far, there are 3 generations of the contrast agent injected during EUS. The most commonly used first-generation agents are Albunex (Nycomed, Oslo), Levovist (Schering, Berlin, Germany), and Echovist (Schering, Berlin, Germany). Second-generation agents are able to pass through the lung vasculature to the systemic circulation, which results in longer perfusion time. In addition, second-generation contrast agents can produce stronger backscatter that is easier to visualize by EUS. There are 3 second-generation contrast agents currently approved in Europe: Optison (Amersham Health, Amersham, England), Sonovue (Braco, Milano, Italy), Luminity (Lantheus Medical Imaging, North Billerica, Massachusetts). None of these agents are approved in United States. Definity (Lantheus Medical Imaging, North Billerica, Massachusetts) is a second-generation contrast agent that is US Food and Drug Administration approved in cardiac echography and was recently used as contrast agent in one of the CE-EUS pilot trials done in the United States through an investigational new drug waiver application. Several studies evaluated the second-generation contrast agents in CE-EUS. In a pilot study by Napoleon and associates of 35 patients with solid pancreatic lesions, the sensitivity, specificity, and accuracy of CE-EUS for differentiating pancreatic adenocarcinoma were 89%, 88%, and 88.5%, respectively. These results were significantly higher than the evaluation with EUS with FNA alone. In a larger trial (156 patients) by Sakamoto and collegues utilizing Levovist as a contrast agent, CE-EUS had significantly higher sensitivity for detecting pancreatic tumors in comparison with CE-CT and power Doppler EUS (80% vs 50% and 11%, respectively). In a recent study that utilized Sonazoid (Daiichi-Sankyo, Tokyo, Japan), a second-generation contrast agent, the overall accuracy of CE-EUS in T-staging of pancreatic cancer was 92.4%. It is possible that, in the future, CE-EUS will have a complementary role with EUS-FNA in evaluating pancreatic lesions. Other potential applications for CE-EUS include differentiating benign from malignant intraductal papillary mucinous neoplasms, although there are not enough data published on this topic yet. In conclusion, CE-EUS technology is very promising and might be integrated into the clinical practice of EUS in the near future.
Detection of Chromosomal Abnormalities in Fine Needle Aspirates
There are situations in which FNA is inconclusive for diagnosis of pancreatic cancer, and new methods for detection of chromosomal abnormalities in the fine needle aspirates were recently introduced in the hope of improving the diagnostic accuracy of FNA. Kubiliun and co-workers performed fluorescence in situ hybridization analysis on FNA specimens when cytology results were inconclusive or not available. Fluorescence in situ hybridization analysis had the sensitivity for detecting pancreatic cancer of 74% in this setting, and the combination of cytology and fluorescence in situ hybridization analysis had a sensitivity of 85%. Mishra and colleagues measured the telomerase activity in the FN aspirate of 40 patients with pancreatic cancer. The addition of telomerase measurement to the cytology results increased the sensitivity for detecting pancreatic cancer from 85% to 98% with specificity of 100%. However, telomerase was not expressed in all pancreatic cancers, only 31 from 40 cases in this study. K-ras mutation was found in 74% of pancreatic cancer patients in 1 study. In a study of 101 patients with pancreatic cancer or chronic pancreatitis, the sensitivity and specificity of K-ras mutation for detecting pancreatic cancer were 70% and 100%, respectively. The drawback of detecting chromosomal abnormalities in FNA specimens is that not all pancreatic cancers express the same mutation. Detection of more than 1 abnormality is needed to slightly increase the sensitivity, albeit with a significant increase in the cost.
Related posts:
Modern Management of Pancreatic Disease
Pancreatic Cystic Neoplasms: Diagnosis and Management
The Surgical Management of Pancreatic Cancer
Modern Treatment of Patients with Chronic Pancreatitis
The Role of Endoscopic Ultrasonography in the Diagnosis and Management of Pancreatic Cancer
Pancreatic Cancer: Medical Management (Novel Chemotherapeutics)
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