Diagnostic precision of endoscopic ultrasound versus contrast-enhanced computed tomography in detection of vascular involvement in pancreatic and periampullary cancers as compared to surgery

Introduction

Periampullary adenocarcinoma refers to tumors that develop from the epithelium in four specific locations around the major duodenal papilla: ampullary adenocarcinoma, distal cholangiocarcinoma, duodenal adenocarcinoma, and pancreatic head adenocarcinoma. Pancreatic ductal adenocarcinoma represents 17% of newly detected cancer cases coming from the digestive tract, with an estimated annual incidence of around 53,000 cases (1).

According to multiple studies, pancreatic ductal adenocarcinoma makes up 50% to 75% of surgically removed cases, whereas distal cholangiocarcinoma and ampullary carcinoma each account for 10% to 20%. Duodenal carcinoma represents 3% to 7% of periampullary adenocarcinoma cases (2,3).

Pancreatic cancer (PC) is a highly lethal form of cancer, with a 5-year survival rate ranging from 8% to 9% (4,5). Currently, there are over 57,600 cases of PC reported each year, making it the fourth most common cause of cancer-related deaths in the United States for both men and women (1).

Surgical excision is the sole opportunity for achieving a cure. Regrettably, less than 10% of people diagnosed with PC have a tumor that can be surgically removed due to delayed presentation. Performing a surgical procedure that successfully achieves complete removal of affected tissue and absence of cancerous cells in the nearby lymph nodes (LNs) results in a higher likelihood of survival (6).

The decision to perform surgical removal of PC depends not only on the size of the tumor, but also on the presence of metastases and the degree of invasion into nearby large blood vessels. These vessels include the common hepatic artery (CHA), superior mesenteric artery (SMA), superior mesenteric vein (SMV), portal vein (PV), celiac artery (CA), splenic artery (SPA), and splenic vein (SPV) (7).

The National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines continue to recommend contrast-enhanced computed tomography (CECT) as the main imaging method for evaluating resectability (8,9).

Endoscopic ultrasound (EUS), a type of endoscopic imaging, provides exceptional clarity and detailed visualization of the pancreas compared to standard computed tomography (CT) scans. EUS, combines an ultrasound transducer with an endoscope to produce detailed and clear images without the need for contrast agents that can be harmful to the kidneys (10). Significantly, EUS plays a crucial role in obtaining tissue samples for diagnosis (via fine needle aspiration or small needle biopsy) and determining the extent of PC in nearby regions. The continuous improvement of EUS techniques has increased its importance as an essential tool for the thorough management, staging, and examination of blood vessels in PC (11-13). EUS is considered a standard imaging method recommended in the ESMO guidelines, although it is not included in the NCCN criteria (9).

This study aims to evaluate the precision of EUS in assessment of resectability of pancreatic and periampullary cancers and identifying degree of vascular invasion. In this study, we evaluated the role of EUS in assessment of resectability of pancreatic and peri-ampullary carcinomas compared to CECT with validation of the results by surgical findings which is considered as the gold standard.

Methods

This study, a prospective cross-sectional one, included 25 patients who were diagnosed with PC or any other periampullary cancer by CECT. Patients were consecutively recruited from the Hepatobillary Units, Internal Medicine and Surgery Departments at Alexandria Main University Hospital between September 2022 and August 2023.

Inclusion criteria entailed patients with a confirmed diagnosis of pancreatic or periampullary cancer via CECT. Exclusion criteria encompassed previous gastric surgery, pregnancy or lactation, prior radiation therapy or chemotherapy, and negative fine needle aspiration biopsy (FNAB) results.

Eligible participants underwent a comprehensive evaluation, which included: (I) a detailed medical history and clinical examination; (II) laboratory tests conducted after fasting overnight, including a complete blood count, liver test profile [alanine transaminase (ALT), aspartate transaminase (AST), international normalized ratio (INR), bilirubin], kidney function tests (urea, creatinine), and tumor markers such as carcinogenic embryonic antigen (CEA) and carbohydrate antigen 19.9 (CA19.9); (III) a CT scan of the abdomen and pelvis to assess the local stage of the disease and evaluate blood vessels, using a pancreatic CT protocol with high-resolution images taken by a 16-channel multi-detector CT scanner; all scans were seen by a single expert radiologist; (IV) an EUS examination performed under general anesthesia by a single, expert endoscopist using a linear echoendoscope (PENTAX EG38-J10UT, PENTAX industry, Alexandria, Egypt) and Hitachi Arietta V60 ultrasound system (Hitachi, Japan). The FNAB procedure was conducted on the pancreatic focal lesion using either 22-gauge or 19-gauge echo tip needles, depending on the availability of needles. The locoregional staging followed the specific criteria outlined in the 8^th edition of the American Joint Committee on Cancer guidelines. The vascular assessment was performed based on the interaction between the tumor and blood vessels, categorized into three types: Type I for direct invasion or encasement, Type II for close proximity, and Type III for no invasion. Types I and II signify the presence of vascular invasion, while Type III indicates the absence of invasion. The vessels that were assessed were determined by the location of the tumor (13); (V) surgical resection of the tumor was then performed by an expert surgeon and the findings presented during surgery was compared to that presented by EUS and CECT.

Resectable form of pancreatic and periampullary cancers is referred as cancers that does not involve the lymphatic or vascular systems and does not have distant metastases. The criteria for determining negative vascular involvement in resectable cancers are as follows: (I) no contact with major arteries such as the aorta, SMA, CA, and hepatic artery, (II) no contact with major veins such as the SMV and PV or their confluence, and (III) tumor encasement of less than 50% of the circumference of the portal and SMVs, or tumor contact with the vein of less than 180 degrees (9,14).

Borderline resectable disease is defined by pancreatic or periampullary cancers with limited involvement of the nearby vasculature (15,16). As per the 2017 NCCN recommendations, borderline resectable PC is characterized by the following criteria: no distant spread of the cancer, involvement of less than 50% of the circumference of an artery or tumor-artery contact of 180 degrees or less with the SMA or CA, and tumor contact with the CHA without invading its bifurcation. Veins are considered to be involved when more than 50% of the circumference of the PV and SMV is surrounded or when there is direct contact between the tumor and the vein measuring at least 180 degrees (9).

Pathological peri-pancreatic LN enlargement, as determined by CECT, was characterized by a minimum size of 8 mm and a rounded form (17). While, pathological LN identified using EUS are characterized by having a size greater than 10 mm, a round form, a distinct border, and a hypoechoic homogeneous pattern (18), FNAB was conducted also on suspicious peri-pancreatic LN. By surgery, LN was defined by histological infiltration of cancerous cells.

Statistical analysis

Data collected were subjected to meticulous revision, organization, tabulation, and statistical analysis through IBM SPSS Statistics (Version 26). Descriptive statistics were employed for categorical and continuous variables, and various statistical tests (e.g., Student’s t-test, Fisher’s exact test) were utilized for comparisons. The Chi-square test was used to assess the diagnostic accuracy (the proportion of correctly classified subjects among all subjects) of the imaging tools vs. surgery. McNemar test used to analyze the significance between the different imaging tools. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of EUS in diagnosing vascular invasion were computed using Excel. Two-sided P values less than 0.05 were considered statistically significant.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board at the Faculty of Medicine, Alexandria University (approval number: 0201610) (date 20/1/2022). Informed consent was obtained from all individual participants included in the study.

Results

Demographic data and baseline characteristics

Overall, 25 patients who were diagnosed with resectable or borderline resectable pancreatic or peri-ampullary carcinomas by CECT were included in this study. The average age was 57.23±10.77 years. The male-to-female gender ratio was almost one (52%/48%). The prevalence of diabetes mellitus (DM), hypertension, hyperlipidemia, smoking, obesity, family history of PC and alcohol were 60%, 52%, 40%, 52%, 80%, 12% and 8% respectively. Most of the patients presented with jaundice (76%), abdominal pain (68%) and weight loss (64%). All this data is presented in Table 1.

Laboratory evaluation

Laboratory data of the studied patients are shown in Table 2.

Site and size of pancreatic and peri-ampullary cancers

Most of our patients included in our study had cancers involving the head of the pancreas (80%), while only 16% had cancers involving the distal end of common bile duct and only 4% had cancers involving the duodenum. The size of tumors measured by EUS (29.16±11.36 mm) and CT (31.12±9.59 mm) exhibited no significant difference as shown in Tables 3,4.

Resectability status of pancreatic and peri-ampullary cancers

Out of the 20 patients who were diagnosed as a resectable cancer by CECT, EUS changed the resectability status for three of them (15%) to become borderline resectable and these results were confirmed by the data presented intraoperatively as shown in Table 5.

Diagnostic precision of CECT and EUS in LN and vascular involvement (Tables 6,7)

The definitive diagnosis of peri-pancreatic LN and vascular involvement was made by surgery. Of note, 14 patients (56%) and 11 patients (44%), were proven to have peri-pancreatic LN and vascular involvement by surgery, respectively.

The rate of correctly diagnosing peri-pancreatic LN involvement by CECT (57.1%) was not significantly higher than the rate of falsely diagnosing them (27.3%) (P=0.94) with sensitivity, specificity, PPV and NPV of 28.6%, 72.7%, 57.1% and 44.4% respectively and an accuracy of 48%. While this rate was much higher using EUS (84.6% vs. 18.2%) (P=0.003) with sensitivity, specificity, PPV, NPV of 78.6%, 81.8%, 84.6%, 75% respectively and an accuracy of 80%. This rate was slightly improved when combining the two modalities together (86.7% vs. 18.2%) (P=0.001) with sensitivity, specificity, PPV, NPV of 92.9%, 81.8%, 86.7%, 90% respectively and an accuracy of 88%.

On the other hand, the rate of correctly diagnosing vascular involvement by EUS (80%) was much higher than that rate by CECT (55.6%) (P=0.04) with a sensitivity, specificity, PPV, NPV, accuracy of 72.7%, 85.7%, 80%, 80%, 80% respectively for EUS and a sensitivity, specificity, PPV, NPV, accuracy of 45.5%, 71.4%, 55.6%, 62.5, 60% respectively for CECT. When we combined the two modalities there was no significant improvement (81.8%) with a sensitivity, specificity, PPV, NPV, accuracy of 81.8%, 85.7%, 81.8%, 85.7%, 84%.

Diagnostic precision of CECT and EUS in venous and arterial vascular involvement (Tables 8,9)

EUS significantly performed better in the diagnosis of venous vascular involvement. Overall, there were 10 patients with surgical involvement of veins (PV, portal confluence, SMV and SPV). The CECT correctly diagnosed only four patients (40%), while the EUS correctly diagnosed seven patients (70%) (P=0.03). On the other hand, there was no significant difference in the rate of arterial involvement (SMA, SPA, gastroduodenal artery and CHA) between CECT and EUS, as there were three patients with surgical diagnosis of arterial involvement. EUS correctly diagnosed two patients (66.7%) while CECT correctly diagnosed only one patient (33.3%) (P=0.2).

The most commonly involved vascular structure is the PV, it was surgically involved in eight patients (32%), followed by the SMV which was invaded in three patients (12%) and two patients with surgical involvement of SMA (8%).

EUS was significantly better when compared to CECT in the diagnosis of PV involvement, it correctly diagnosed five patients (62.5%) while CECT correctly diagnosed only three patients (37.5%) (P=0.04). There was no difference between the EUS and CECT regarding the detection of other vessels, both EUS and CECT identified two patients (66.7%) with SMV involvement and one patient (50%) with SMA involvement.

Discussion

PC is a highly challenging kind of cancer with a poor prognosis. It is characterized by a 5-year survival rate of less than 10% in the USA (19). Only a small group of patients are fortunate to receive an early-stage PC diagnosis, which allows them the option of drastic surgical intervention. However, even in such conditions, the 5-year survival rate finds it difficult to exceed the 20% benchmark (20). An exact assessment of the complex correlation between tumors and blood vessels is crucial in establishing the operability of PC and forecasting its prognosis. Although CECT is now regarded as the most reliable method for the initial evaluation of PC, there are certain constraints associated with its use. Some patients are unable to undergo CT examination with intravenous contrast due to variables such as allergic reactions or compromised kidney function (7). It is important to mention that around 0.6% of people experience allergies to contrast medium. Within this particular framework, EUS serves as a valuable instrument that can thoroughly evaluate PC and determine the presence of vascular invasion without the requirement of contrast agents (10,11,21).

CECT and EUS are the current primary imaging methods used to determine the extent of PC and peri-ampullary malignancies (22). While the CECT scan with intravenous contrast material injection is commonly used as the standard imaging tool for local staging of these tumors, there are studies that support the use of EUS in this context (23). In this study, we evaluated the relative diagnostic precision of EUS and CECT in detecting the local spread of PC and peri-ampullary cancer, as compared to the definitive surgical findings considered as the gold standard.

Dahiya et al.’s comprehensive survey conducted across the United States from 2008 to 2017 revealed a significant change in the prevalence of PC over time, specifically in relation to gender. In 2008, there was a small majority of females, while in 2017, there was a little majority of males (24). In addition, Cai et al. highlighted that PC primarily affects older individuals, with a median age of 70 years at the time of diagnosis. Notably, the proportion of patients identified before the age of 55 years is extremely small (25). The study conducted by Dahiya et al. highlights the importance of age-related factors in the epidemiology of PC, specifically in the age group of 65–79 years. The research shows a rising incidence of hospitalizations in this age group owing to PC (24). Matsuda’s explanation of age-related telomere disruption offers a possible explanation for the higher occurrence of PC in older individuals (26).

The study conducted by Lugo et al. provided valuable insights into the correlation between smoking and the risk of PC, revealing a significant increase in risk even with minimal tobacco usage. This observation strengthens our findings about the increased risk linked to smoking (27). In the current study, the main symptoms of PC were primarily obstructive jaundice (76%) with four of these patients (20%) were endoscopically drained before surgery, the next presenting symptom was abdominal pain (68%). The study conducted by Gohar et al. produced slightly varied findings. Abdominal discomfort was reported as the most prevalent symptom, accounting for 75% of cases, followed by obstructive jaundice at 21.1% (28). The differences in clinical presentation can be due to the varied sample sizes throughout the studies.

There was variation in site distribution between the current work and that of Fujii, this could be attributed to differences in patient cohorts and geographical disparities. In addition, the current study found a tumor size ranging from 15 to 54 mm, whereas Fujii et al. discovered a smaller tumor size ranging from 18 to 33 mm (21).

Regarding peri-pancreatic LN and overall vascular involvement, there have been only a limited number of studies that have investigated this matter. Significantly, the systematic review and meta-analysis conducted by Dewitt et al. included 11 meticulously conducted studies involving a total of 678 individuals. The findings revealed that both CECT and EUS demonstrated similar diagnostic accuracy in terms of local nodal staging and overall vascular invasion (29). Other studies, unlike our study, have reported that CECT is superior to EUS in the diagnosis of vascular involvement, these studies were conducted by Soriano et al. and Ramsay et al. (30,31). Regarding peri-pancreatic LN involvement, the current study demonstrated that the diagnostic performance of EUS for diagnosis of peri-pancreatic LN showed a sensitivity of 78.6%, PPV of 84.6% and an accuracy of 80% compared to 28.6%, 57.1% and 48% for CECT respectively. This was supported by a study conducted by Gress et al. which showed that EUS has a diagnostic accuracy of 72% in identifying peri-pancreatic LN as compared to only 55% by CECT (32).

Regarding venous involvement, Marty et al. showed that EUS is equal or slightly superior to CECT with a sensitivity of 56% (33). On the contrary, we showed a higher diagnostic performance of EUS for venous involvement with a sensitivity of 70%, specificity of 93.3% and PPV of 87.5% and this is in cope with previous studies, reporting similar results like those conducted by Rösch et al. and Palazzo et al. (34,35). Remarkably, EUS was superior to CECT in diagnosing venous vascular involvement, although there was no disparity in the diagnostic precision for arterial vascular involvement. The results of the current study align with earlier studies that have demonstrated the superior efficacy of EUS in detecting venous vascular invasion (21,36). The improved ability to identify venous vascular involvement may be attributed to the close proximity of the PV, SMV, and PC to the EUS transducer (37).

Unfortunately, some cases are still missed by EUS, this could be attributed to the operator dependence of EUS and anatomic variations of the celiac and superior mesenteric arteries and limited number of experienced EUSonographers (6).

The current work highlighted the diagnostic precision of EUS in evaluating the presence of venous and arterial invasion as well as LN involvement in pancreatic and peri-ampullary cancers. EUS exhibited a high level of sensitivity, specificity, PPV, NPV, and accuracy, which were consistent with the findings of Fujii et al. (21), this could be attributed to the growth of learning curve for the endoscopist, availability of doppler examination which clearly verifies vascular relation, proximity of the US probe to the tumor and degree of magnification (6). The data emphasize that EUS is a dependable substitute for CT, especially due to its capability to obtain tissue samples and avoid the need of contrast agents. CECT has few limitations in detection of vascular involvement in these types of cancer, to mention few, CECT is subjected to artificial artifacts, it is more subjected to interobserver agreement and for a proper evaluation of pancreatic lesions and adjacent vascular structures, both the pancreatic phase (40–50 seconds from intravenous contrast injection) and venous phase (65–70 seconds) should be included, which may subject to human fallacies (6).

The current study could be considered highly specific as we compared the findings presented by EUS and the CECT to the definitive surgical findings which is the gold standard. This adds more value to the study as the studies comparing the diagnostic modalities to surgical findings are limited.

The primary limitations of the current study are the limited number of patients involved but this is mainly because of its prospective nature and the exclusion of individuals who were discovered to have non-resectable or metastatic cancers during the evaluation process. While their exclusion may create bias, they cannot be included because they cannot undergo surgical resection, which was highly crucial in our study. The same goes for patients who received neoadjuvant chemotherapy, as the size of the cancer and its relationship to nearby blood vessels could be affected thus affecting the results of our study.

Conclusions

The findings presented in this study indicate that EUS was more precise than CECT in accurately determining the extent of PC and peri-ampullary cancer within the local area. EUS demonstrated a greater level of diagnostic accuracy in identifying both peri-pancreatic LNs and blood vessels involvement especially the PV. Combining both modalities could potentially enhance the precision of diagnosing vascular involvement and detect the resectability status of these cancers more precisely. Considering the potential benefits it offers, the integration of EUS examination as a primary diagnostic tool for assessing pancreatic and periampullary cancers preoperatively should be given serious consideration. This approach has the potential to enhance patient care and decide the best treatment strategy for these patients.

Acknowledgments

Funding: None.

Footnote

Data Sharing Statement: Available at https://apc.amegroups.com/article/view/10.21037/apc-24-12/dss

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-24-12/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-24-12/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board at the Faculty of Medicine, Alexandria University (approval number: 0201610) (date 20/1/2022). Informed consent was obtained from all individual participants included in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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