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Keywords:

  • cancer staging;
  • diagnosis;
  • endoscopic ultrasonography;
  • epidemiology;
  • pancreatic cancer

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References

In Asia, the incidence of pancreatic cancer in some countries has been increasing. Owing to most cases being diagnosed late, prognosis for pancreatic cancer remains dismal. It is clear that the future for pancreatic cancer lies in early detection. While the possible presence of pancreatic masses is often first raised by non-invasive abdominal imaging, such as computerized tomography and magnetic resonance imaging, smaller lesions and locoregional lymph node metastases are often not detectable by these means. Endoscopic ultrasonography (EUS) offers a higher sensitivity (93–100%) for detection of small potentially curable pancreatic masses than other existing imaging modalities. It is also recommended for the evaluation of portal vein confluence, portal vein, celiac axis, and superior mesentric artery origin, and exclusion of resectability. Due to the closer proximity of EUS to the target structure, and lower rate of needle tract seeding, EUS-guided fine-needle aspiration of pancreatic mass is considered the most suitable tissue acquisition technique. Lastly, EUS also enables the performance of endoscopic interventions. Its performance can be further enhanced with newer techniques, including contrast-enhanced ultrasound and elastrography. It is anticipated that in the near future, molecular technologies may make it possible to detect microscopic amounts of cancer in tissue or blood, predict relapse and survival after therapy, as well as determine optimal therapy.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References

Most cases of pancreatic masses are neoplastic, primarily ductal adenocarcinoma. Among the non-neoplastic pancreatic masses, the important ones include chronic focal pancreatitis, autoimmune pancreatitis, and masses due to infection like tuberculosis.[1-3] Less common neoplasia includes neuroendocrine tumor, lymphoma, and metastases. Pancreatic cancer is the fourth and fifth most common cancer in men and women, respectively.[4, 5] It is the eighth leading cause of cancer death in the world, ranking thirteenth in incidence. Overall, about 70% of pancreatic cancers develop in the pancreatic head, and 10–20% develop in the body and tail.[6] Most cases of pancreatic cancers are diagnosed at an advanced stage, at which point the tumor may not be amenable to surgical resection. At the time of diagnosis, 52% of all patients have distant disease, and 26% have regional spread.[7] Prognosis for pancreatic cancer is dismal, with overall 5-year survival rate of about 5–6%. The suspicion for pancreatic cancer is often first raised by abnormal findings from abdominal imaging, for example computerized tomography (CT) and magnetic resonance imaging (MRI), or other cross-sectional imaging modalities, but smaller lesions and locoregional lymph node metastases are often not detectable by these means. Endoscopic ultrasonography (EUS), with the ability to endoscopically access and image the pancreatico-biliary ductal system at close proximity, and the option to acquire tissue samples through EUS-guided fine-needle aspiration (EUS-FNA) for histopathologic analysis, offers a better solution for the detection of smaller, potentially curable lesions. This review will discuss the epidemiology and the diagnostic evaluation of pancreatic tumor in Asia, with emphasis on the use of EUS and EUS-FNA.

Epidemiology of pancreatic cancer in Asia

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References

The age-standardized rates (ASR) of pancreatic cancer in most Asian countries are lower than those in the West, with the lowest rate reported in South-Central Asia and highest in some countries in Northeastern Asia (Table 1).[4, 5] In the more developed nations like Japan and South Korea, the incidence rates have risen over the decades to approximate the rates in the West.[8] Based on year 2008 data,[5] the ASR of pancreatic cancer for men in Japan (10.0 per 100 000) has already overtaken the rates for Western countries like the United States (ASR: men, 8.0; women, 6.1) and Europe (ASR: men, 7.8; women 5.0). In Japan, the increase in incidence is largely attributed to the aging population. In contrast, the ASR of pancreatic cancer in India is among the lowest in the world (ASR: men, 1.1; women 0.8).[4, 9] In the Southeast Asian region, Brunei has the highest incidence of pancreatic cancer (ASR: men, 5.5; women, 4.6), followed by Singapore, with ASR for men and women at 5.1 and 3.7 per 100 000, respectively.[2, 10, 11] The incidence rates have been increasing since the late 1960s. In contrast, the incidence of pancreatic cancer in Malaysia, Thailand, and the Philippines remains low, with marginal changes in the last decade.[5, 11] Mortality rates are generally low or moderate in the region (0.9–4.4%), except for Japan (7.1%) and South Korea (5.4%) where the rate approximates or even exceeds that of Europe (6.2%) and America (5.2%) (Table 1).[5, 7] Significant increase in mortality rate has been reported for both Korean men and women (P < 0.001), and for Japanese women (P < 0.02).[12] India, which has the lowest incidence of pancreatic cancer, also recorded the lowest mortality rate (0.9%).

Table 1. Age-standardized rate (ASR) of incidence of pancreatic cancer and mortality rate in various Asian countries and regions
Asian countriesPopulationMalesFemalesPopulation
IncidenceMortality
ASRaASRaASRaASRa
  1. a

    A rate is the number of new cases or deaths per 100 000 persons per year. An ASR is the rate that a population would have if it had a standard age structure.[5]

Philippines22.31.81.8
Thailand1.41.71.11.1
Malaysia2.12.51.82.1
Singapore4.45.13.74.4
Brunei55.54.63.9
Indonesia2.83.12.52.7
China2.83.22.42.5
South Korea6.284.75.4
Japan7.9106.17.1
India11.10.80.9
Asian regions
Asia2.73.22.32.5
Eastern Asia3.84.53.23.5
South-Eastern Asia22.31.81.9
South-Central Asia1.11.20.91
Western Asia3.43.92.93.2
X
Europe Region6.37.856.2
Americas5.66.24.95.2
United States786.16.2

Apart from geographical differences, ethnic differences in the incidence of pancreatic cancer have been noted. In Malaysia, the ASR of pancreatic cancer in Chinese men (2.4 per 100 000) was found to be higher than that of the Malays (1.0 per 100 000) and the Indians (1.3 per 100 000).[12] Similarly in Singapore, incidence of pancreatic cancer in Chinese is found to be higher than that of the Malays and the Indians.[13]

Role of EUS in the diagnosis and evaluation of pancreatic tumor

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References

Currently, the only curative treatment for pancreatic cancer is surgical removal. Unfortunately, only a very small percentage of patients are amenable to such treatment. The pancreatic cancers that are operable are those that have not significantly invaded into any surrounding structures.[14] Given the fact that operable pancreatic cancers are small in diameter, the current non-invasive techniques, including CT scanning and MRI, cannot provide sufficient resolution to reliably detect such lesions. EUS, having higher resolution, plays a significant role in the identification of these small pancreatic lesions. Moreover, EUS is able to stage tumor and allow tissue acquisition via FNA. It is also useful for the assessment of local blood vessel involvement and detection of locoregional lymph node metastases, which help in the staging of the cancer.

Identification of pancreatic cancer

Studies that used imaging to detect pancreatic lesions have shown EUS to yield a high level of sensitivity, ranging from 93% to 100%,[15-23] which is higher than that of CT scan, particularly with small diameter pancreatic lesions (Fig. 1)[14-19, 23-26] While the efficacy of CT scan has progressively increased over the years, it remains substantially inferior to the efficacy of EUS. The few studies that described multi-detector CT also confirmed lower detection rate of small pancreatic masses when compared with EUS.[23-25] However, EUS has the limitations of being an invasive technique and is operator-dependent. Thus, CT scan is still recommended as the first-line imaging to detect pancreatic lesions. In the event of a negative result with CT scan, EUS is indicated to confirm the absence of small pancreatic lesions in patients with a clinical suspicion of pancreatic cancer as it has a 100% negative predictive value.[22]

figure

Figure 1. The sensitivity of endoscopic ultrasonography (EUS) and computerized tomography (CT) scan in the identification of pancreatic lesions. (image) EUS; (image) CT.

Download figure to PowerPoint

Pancreatic cancer generally displays as a hypoechoic lesion on EUS, and can thus be readily differentiated from the homogeneous “salt and pepper” appearance of the surrounding pancreatic parenchyma. However, in patients with chronic pancreatitis where the pancreatic parenchyma displays heterogeneous echogenicity, the presence of small pancreatic lesions may be missed. A multicenter retrospective study reported EUS' missed detection of pancreatic lesions in 20 patients, among whom 12 had chronic pancreatitis.[27] In summary, EUS is the most reliable imaging technique for the identification of pancreatic lesions. Its detection rate of pancreatic lesions can be further enhanced with newer techniques, including contrast-enhanced ultrasound and elastrography.[28, 29]

Tumor staging

Current staging of pancreatic cancer follows the TNM Classification of Malignant Tumors. T4 pancreatic cancer is generally considered unresectable, whereas T3 tumors are operable. The distinction between T3 and T4 stages is, therefore, critical, and the typical criterion used to delineate such tumors is the invasion of the main artery. Portal vein (PV) or superior mesenteric vein invasion by pancreatic cancer at T3 staging is typically still considered operable; however, in cases where venous invasion is extensive, the tumors may be judged as inoperable, depending upon the expertise of the surgeon. While CT scan is generally suited for arterial or venous invasion evaluation, EUS has proven to be more accurate in detecting PV or splenic vein invasion, with an accuracy rate of 78–98%, especially in the area of portal confluence, because it can image at closer proximity to the area and provide a higher resolution than CT scan.[19, 30-32] Any degree of arterial invasion is staged as T4, indicating a condition that cannot be curatively treated with surgical removal. CT scan has the capability of detecting arterial invasion over a broader area, in particular in the region of superior mesenteric artery, where CT is a more superior imaging technique, with a sensitivity rate at 71% versus that of 57% by EUS.[32] Thus, CT scan is recommended as the primary imaging technique for pancreatic cancer staging. However, if the tumor is considered potentially operable by the CT scan, it should be further evaluated by EUS to confirm the operability so as to avoid unnecessary risk or complications from the ensuing surgery.[33]

EUS-FNA

Despite the various imaging modalities available for predicting if a pancreatic mass is benign or malignant, pathological diagnosis is mandatory to definitively assess whether the mass should be resected or not, particularly in cases where lymphoma, tuberculosis, or autoimmune pancreatitis are suspected. Tissue diagnosis is typically obtained by either percutaneous FNA or EUS-guided FNA. EUS confers several advantages over percutaneous FNA. First, it can be operated in closer proximity to the pancreas, thus enabling a higher degree of resolution.[34] Second, EUS alleviates the risk of inadvertent puncturing of the intervening organs in order to access the tumor site. Finally, in potentially resectable masses, avoidance of needle tract seeding is considered critical. EUS is a valid technique in cases where the mass is located in the pancreatic head, necessitating puncturing through the duodenal wall, which will have to be removed anyway during the ensuing Whipple's operation should the tumor proves to be malignant. In comparison with percutaneous methods, EUS is the preferred technique for obtaining pancreatic head mass tissue as it minimizes the theoretical risk of needle tract seeding. Prior study had demonstrated that CT-guided FNA has a risk of carcinomatosis peritonei of 16.3%, whereas the EUS' associated risk is just 2.2%.[35]

The efficacy of EUS-guided FNA in the diagnosis of solid pancreatic mass has been studied in a recent meta-analysis of 33 studies including 4984 patients. The results showed that if atypical and suspicious results were considered malignant, the pooled sensitivity, specificity, positive predictive value, and negative predictive value were 91%, 94%, 98%, and 72%, respectively. In view of the low negative predictive value, a negative EUS-FNA result cannot exclude the presence of malignancy.[36] Several confounding factors can influence the diagnostic value of EUS-FNA. These are diameter of the needle, consistency of the lesion, number of passes, and availability of onsite cytopathologist. While more tissue could be obtained with a larger-sized needle, a recent retrospective study from Japan demonstrated comparable diagnostic yield between a 22- and 25-G needle;[37] this was confirmed by another study.[38] More recently, Siddiqui et al. performed the first randomized, controlled trial comparing 22-G with 25-G needles for EUS-FNA, and found a nonsignificant trend toward a higher diagnostic yield with 25-G needles compared with 22-G needles (95.5% and 87.5% respectively; P = 0.18).[39] Bang et al. in a recent randomized study compared the use of 22-G aspiration and 22-G biopsy needles in patients with solid pancreatic masses, and found no significant difference in yield or quality of the histologic core between the two needle types.[40] We await trial results to see if the capillary method of obtaining tissues offer better diagnostic yield.

Onsite pathologist is probably the most important factor determining the success of EUS-FNA result.[41] Regarding tissue preparation, liquid-base cytology is thought to be better than conventional smear method; however, a recent prospective study from Korea showed that the former was less accurate.[42] Another large recent study also confirmed higher accuracy rate of conventional smear compared with ThinPrep method, at 98% versus 64%, respectively.[43]

In the setting of chronic pancreatitis, the efficacy of EUS-FNA is significantly lower than that in normal pancreatic parenchyma. This is due to the increased difficulty in aspirating from the harder fibrotic tissue, resulting in what is termed dry tap.[44, 45] As dry tap can also occur in malignant masses with hard consistency, a situation that could happen in the setting of de novo pancreatic cancer or in pancreatic cancer secondary to chronic pancreatitis, it is not a reliable indicator for nonmalignancy.

In summary, EUS has a higher sensitivity for detection of small pancreatic masses than other existing imaging modalities. While CT scan appears to have a similar degree of accuracy when compared with EUS in tumor staging for the evaluation of tumor resectability, EUS examination is still recommended to evaluate PV confluence, PV, celiac axis, and SMA origin, and exclude resectability. Lastly, due to the closer proximity of EUS to the target structure, and lower rate of needle tract seeding, EUS-FNA of pancreatic mass is considered the most suitable tissue acquisition technique. A negative FNA result cannot be considered as true negative, particularly in a setting of high pretest likelihood. Further systematic research is required to improve the overall accuracy of EUS-FNA.

Figure 1 depicts the sensitivity of EUS and CT scan in the identification of pancreatic lesions.

Complications of EUS and EUS-FNA of solid pancreatic tumor

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References

EUS without FNA biopsy has been shown to be safe. The most dreaded complication following this procedure is perforation, which was reported to occur in 0–0.4% of cases following EUS.[46, 47] Other complications included cardiopulmonary events and allergic reactions to medications. The reported complications following EUS-guided FNA range 0–2.5%.[48-52] Among these, pancreatitis occurs in 1.2–2% of the cases.[53, 54] Bleeding following EUS-FNA can occur intraluminally or extraluminally. The reported rate of intraluminal bleeding as a complication of EUS-FNA is 1–1.3%.[51, 53] A study looking into acute extraluminal hemorrhage following EUS-guided FNA in a group of 227 patients reported three (1.3%) cases manifesting as expanding echo-poor region adjacent to the sampled lesion. All three patients were treated with antibiotics and were observed as outpatients.[55]

The occurrence of EUS-FNA-related complications may be related to the endosonographer's experience. Eloubeidi et al. reported a higher minor complication rate of 13–18% in the first 200 EUS-FNA cases that he performed versus 7% in the next 100 cases.[56] However, the rate of major complications was the same at 1–3% in the two periods of training. A larger-sized needle does not appear to increase the complication rate. For example, in a randomized study of 131 patients who underwent EUS-FNA using either a 22G and 25G needle, no complication developed in either arm.[39] The use of 19G trucut biopsy needle was reported to have a complication rate of 0.6–2%, which is not increased compared with that reported with smaller-gauge needles.[57, 58] Smaller needles could offer advantages in causing less trauma, and thus less bleeding as well as better passage in angulated endoscope position. Fine-aspiration needles may be more sensitive in fibrotic lesions because of their tendency to preferentially dislodge the tumor cells and leave the denser surrounding stroma behind.

Future and advanced technologies in the diagnosis of pancreatic masses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References

While EUS-FNA has a sensitivity of 85–90% and a specificity of almost 100% in the diagnosis of pancreatic masses,[59-61] lower (< 75%) sensitivity is reported when there is a coexistent presence of chronic pancreatitis.[59, 60] Better technologies or techniques are therefore needed to address this issue.

Imaging technologies

Contrast harmonic EUS (CHEUS)

CHEUS is now available in clinical practice with the development of second-generation ultrasonic contrast agents (examples are Sonovue, Sonazoid, and Definity) containing inert gases, and the availability of appropriate EUS processors and endoscopes. These ultrasonic contrast agents consist of a solution of microbubbles that can be injected intravenously to reach the target structures of interest. When the microbubbles within the vessels are hit by an ultrasonic wave, the vibration creates a strong backscattered acoustic shadow that is detected and reproduced as an opacification. Vascular structures are thus highlighted as hyperechoic. In this way, the interface between a major vessel, the vascular wall, and adjacent mass becomes clearer, and the absence or presence of vascular invasion can be more clearly determined. The differences in the vascularity and microvascular pattern of different pancreatic lesions will result in differences in CHEUS appearance, thus facilitating diagnosis. A vascular lesion will be expected to enhance uniformly, whereas a hypovascular lesion, such as pancreatic adenocarcinoma, which is rather fibrotic, may be expected to enhance less, and even exhibit, abnormal tumor vessels. Conversely, inflammatory masses are more hyperemic, and hence would be expected to appear hyperechoic with CHEUS. Published studies have shown CHEUS to be useful in the detection and differentiation of pancreatic lesions, and in the assessment of T staging.[60-65] A recently published meta-analysis reported that the pooled sensitivity of CHEUS for the differential diagnosis of pancreatic adenocarcinomas was 94% (95% confidence interval [CI], 0.91–0.95), and the specificity was 89% (95% CI, 0.85–0.92).[60]

EUS elastography

EUS elastography is a technology that measures tissue elasticity of targeted structure. It has been applied to gauge the hardness of pancreatic mass and help differentiate pancreatic cancer, which is harder than an inflammatory lesion.

The software used to interpret EUS elastography has evolved over three generations: the first-generation software recognizes color pattern, the second-generation includes a quantitative assessment (strain ratio), and the third-generation utilizes computer to generate hue histograms.[65] Using the first-generation software, two large retrospective and one prospective studies reported sensitivity, specificity, and accuracy rates, ranging from 92.3% to 100%, 64.3% to 85.5%, and 89.2% to 94.0%, respectively.[66-68] In the case of the second-generation software, its sensitivity, specificity, and accuracy rate was reported to be 100%, 92.9%, and 97.7%, respectively, in a prospective study.[69] For the third-generation software, a prospective, multicentered study reported a sensitivity rate, specificity rate, and positive and negative predictive value at 87.6%, 82.9%, 96.3%, and 57.2%, respectively.[70] Thus, while EUS elastography seems to have a modest diagnostic value for discriminating pancreatic masses, it is still not good enough as a stand-alone tool to definitively diagnose pancreatic lesions. In light of this, further studies on the precise role of EUS in the diagnosis of pancreatic masses in the setting of chronic pancreatitis or incidentally discovered pancreatic mass need to be undertaken.

Digital image analysis (DIA)

DIA is the extraction of meaningful information from digital images by means of image processing techniques. A computer program is used to analyze EUS images and differentiate pancreatic malignancy from focal pancreatitis. After the program is uploaded with representative images, it scans rows of gray-scale pixels from the digitized representative areas of internal echo structure, and is “taught” as to which of them are benign and which are malignant.[71] The program then attempts to differentiate malignant from benign inflammatory lesions in the pancreas on the basis of pixel characteristics. In 2001, Norton et al. used neural networks analysis of EUS images and were able to differentiate focal pancreatitis from malignancy with 89% accuracy.[72] More recently, Das et al. used another neural network-based predictive model and concluded that DIA of texture features of EUS images was highly accurate in differentiating pancreatic cancer from chronic pancreatitis and normal tissue with an area under receiver operating characteristic curve of 0.93.[73] Although DIA is not ready to replace the gold standard histology currently, it may preferentially select a region within a mass to target for FNA for better cellular yield. DIA may also improve the interobserver variability in the interpretation of EUS images. Another potential application of DIA may be in differentiating viable tumor from necroinflammatory changes after chemotherapy and radiation therapy.

Molecular diagnostics

Three major areas are emerging: (i) molecular diagnostics to detect microscopic amounts of cancer in tissue or blood; (ii) molecular prognostics to predict relapse and survival after therapy; and (iii) molecular predictors to directly determine optimal therapy.

Mutations of the K-ras and p53 genes have been found in a large proportion of pancreatic cancers, which has sparked interest in the detection of these mutations from tissue specimens obtained from EUS-FNA of pancreatic masses and pancreatic juices. Conventional cytology had an overall accuracy of 71–91% compared with 82–84% in K-ras mutation analysis. When the two methods were combined, the overall accuracy increased to 85–98%.[73] However, K-ras mutations have also been detected in chronic pancreatitis and premalignant conditions, for example intraductal papillary mucinous neoplasm. In addition, up to 20% of pancreatic cancers do not carry the K-ras mutations. Khalid et al. applied the loss of oncogene heterozygosity analysis to solid pancreatic tumors and pancreatic cysts.[74, 75] Preliminary results suggest that this may allow accurate detection of cancer, although the role of prognosis is less well established.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References

In Asia, the overall incidence of pancreatic cancer is lower than that in the West, but rising incidence rate is reported in Japan and Korea. Despite medical advances, prognosis for pancreatic cancer remains dismal. Thus, the future for pancreatic cancer lies in early detection. Although CT is often the first-line imaging to raise suspicion of pancreatic tumor, EUS and EUS-FNA are the modalities of choice for staging and tissue acquisition of pancreatic cancer. It is anticipated that newer EUS-based imaging technologies and molecular technologies may make it possible for us to detect early cancer, predict relapse and survival after therapy, as well as determine optimal therapy.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Epidemiology of pancreatic cancer in Asia
  5. Role of EUS in the diagnosis and evaluation of pancreatic tumor
  6. Complications of EUS and EUS-FNA of solid pancreatic tumor
  7. Future and advanced technologies in the diagnosis of pancreatic masses
  8. Conclusion
  9. References
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