Role of Endoscopic Ultrasound in Staging and Vascular Assessment of Pancreatic Cancer

Introduction Computed tomography (CT) of the abdomen with contrast stands as the gold standard for assessing pancreatic cancer, encompassing both staging and vascular analysis. However, not all patients are suitable candidates for contrast-enhanced CT (CECT) scans due to factors such as contrast agent allergies, pregnancy, renal impairment, radiation risks, and limited tissue sampling capability in CECT scans of the abdomen. In light of these challenges, this study evaluated the diagnostic capabilities of endoscopic ultrasound (EUS) compared to CECT for staging and vascular assessment of pancreatic cancer. Methods Fifty patients diagnosed with pancreatic cancer underwent evaluations using both CECT scans and EUS, focusing on staging and vascular invasion assessment. Vascular evaluation was carried out using a categorization system based on EUS findings, classifying them into three types based on the tumor-vessel relationship: Type 1 indicating clear invasion or encasement of a vessel by a tumor or contact with a vessel wall exceeding 180 degrees, Type 2 representing abutment, wherein a tumor contacts a vessel wall but at an angle less than 180 degrees, and Type 3 implying clear non-invasion, where a discernible distance exists between a tumor and a vessel. In this categorization, Type 1 and Type 2 indicated signs of vascular invasion, while Type 3 indicated vascular non-invasion. These findings were subsequently compared to the results from CECT scans. The endoscopist performing EUS was blinded to the CT outcomes prior to the examination. Results Regarding pancreatic cancer staging, EUS exhibited remarkable sensitivity, specificity, and accuracy rates of 100% according to the T criterion.As for vascular invasion assessment, EUS demonstrated sensitivity, specificity, and accuracy of 100%, 95.93%, and 96%, respectively, for venous invasion. For arterial invasion, the figures were 95.65% sensitivity, 100% specificity, and an overall accuracy of 99.5%. Conclusion EUS is an effective modality for evaluating both staging and vascular invasion in pancreatic cancer, boasting exceptional sensitivity, specificity, and accuracy rates. The findings are robust enough to consider EUS a viable alternative to CT scans in evaluation, with the added advantage of EUS offering tissue sampling capability.


Introduction
Pancreatic cancer stands as a malignancy characterized by a dismal prognosis, boasting a mere five-year survival rate that scarcely surpasses 10% [1].Globally, it ranks as the sixth most prevalent cancer and constitutes the third principal cause of cancer-induced mortality in the United States, further attesting to its profound impact [2].The potential for curative intervention lies primarily in surgical resection with sufficient safety margins when metastatic lesions are absent.Regrettably, the diagnosis of this malignancy frequently transpires in advanced stages, thereby rendering surgical intervention feasible only in a confined subset of cases [3].
The decision to proceed with surgical resection of pancreatic cancer pivots not solely on tumor dimensions but substantially on the presence of metastases and the extent of invasion into contiguous major vessels, which encompass a range including 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) [4].Although CT with intravenous contrast administration currently reigns as the gold standard for the initial staging of pancreatic cancer, certain patients are precluded from undergoing contrast-enhanced abdominal CT examinations due to contraindications like contrast agent allergies, compromised renal function, and pregnancy [5].
Endoscopic ultrasonography (EUS), a form of endoscopic imaging, affords unparalleled resolution and intricate depiction of the pancreas when contrasted with conventional CT scans.Integrating an ultrasound transducer onto the endoscope, EUS generates meticulous and unhindered imagery devoid of nephrotoxic contrast exposure [6].Notably, EUS is pivotal in diagnostic tissue sampling (fine needle aspiration or fine needle biopsy) and the regional staging of pancreatic cancer.The progressive refinement of EUS methodologies has amplified its significance as an indispensable instrument for the comprehensive management, staging, and vascular scrutiny of pancreatic cancer [7][8][9].However, consensus concerning the precise role of EUS in the primary evaluation of pancreatic cancer remains elusive [5].
Henceforth, the present study has been conceived with the specific objective of assessing the diagnostic efficacy of EUS in the context of pancreatic cancer staging and the discernment of significant vascular invasion.A comparative analysis with contrast-enhanced abdomen CT shall be undertaken to elucidate the potency of EUS in these critical dimensions.
This article was previously posted to the Research Square preprint server on December 29th, 2022.

Study design
This investigation adopts a cross-sectional design to assess the diagnostic prowess of endoscopic ultrasound (EUS) in pancreatic cancer staging and vascular evaluation, juxtaposed against contrast-enhanced computed tomography (CECT).

Setting and duration
Conducted at the Al-Ibrashi Endoscopy Unit within the Internal Medicine Hospital of Cairo University, this study spanned from January 2020 to October 2022, with an exclusion period from March 2020 to September 2020 due to the facility's temporary transformation into an isolation center for COVID-19 patients.

Participants
Out of 89 patients identified with pancreatic focal lesions through abdominal ultrasound, 50 individuals were selected based on subsequent histopathological confirmation of pancreatic cancer by fine-needle aspiration biopsy (FNAB).Inclusion criteria entailed a minimum age of 18 years and a confirmed diagnosis of pancreatic cancer via FNAB.Exclusion criteria encompassed age below 18 years, previous gastric surgery, pregnancy or lactation, prior radiation therapy or chemotherapy, contraindications to CECT, including chronic renal failure or contrast material allergy, and negative FNAB results for malignancy.

Workup
Eligible subjects underwent comprehensive evaluation, which encompassed: (1) thorough medical history and clinical examination; (2) laboratory investigations following overnight fasting, including complete blood count, liver function tests (alanine transaminase (ALT), aspartate transaminase (AST), international normalizing ratio (INR), serum bilirubin), renal function tests (urea, creatinine), and tumor markers such as CEA and CA19.9; (3) CECT of the abdomen and pelvis for locoregional staging and vascular appraisal, employing a pancreas CT protocol involving triphasic imaging with thin slices using a 16-channel multidetector CT scanner; (4) EUS examination under general anesthesia utilizing a 7.5 MHz echoendoscope (Pentax FG 38UX or Hitachi ultrasound EUB 525).Based on needle availability, FNAB from the pancreatic focal lesion was performed using echo tip needles of either 22 gauge or 19 gauge.Locoregional staging adhered to the general guidelines of the American Joint Committee on Cancer 8th edition.Vascular evaluation was conducted in accordance with the tumor-vessel relationship, stratified into three categories: Type I for clear invasion or encasement, Type II for abutment, and Type III for non-invasion.Types I and II indicated vascular invasion, whereas Type III indicated non-invasion.The specific vessels evaluated depended on the tumor's location.

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.Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of EUS in diagnosing vascular invasion were computed using Excel.

Demographic characteristics and presenting symptoms
In this cross-sectional study, the mean age of the enrolled patients was 62.32 ± 7.82 years, with 72% (n=36) male and 28% (n=14) female.Among the study participants, 64% (n=32) were smokers.The most common presenting symptom was jaundice, which was observed in 66% (n=33) of patients, followed by abdominal pain in 22% (n=11), incidental discovery in 10% (n=5), and abdominal swelling in 2% (n=1) as shown in Table 1 and Table 2

Laboratory investigations
Laboratory data of the studied patients are shown in Table 3.  Laboratory investigation of the studied patients presented as mean ± SD and median and range.

Site and size of pancreatic cancer
The most frequent site of pancreatic cancer was the head of the pancreas at 48% (n=24), followed by the head and neck at 26% (n=13), head and uncinate at 18% (n=9), and the body of the pancreas 8% (n=4).The size of pancreatic tumors measured by EUS (36.26 ± 14.38 mm) and CT (35.52 ± 14.47 mm) exhibited no significant difference, as shown in Table 4 and Table 5.

Site Frequency (n) and the percentage(%)
Head

Vascular invasion assessment
In the evaluation of vascular invasion, there was no significant difference between CT and EUS findings for the vessels assessed, which included the SMA, SMV, PV, hepatic artery (HA), CA, SPV, and SPA (Table 8).

Accuracy of EUS in vascular invasion
The diagnostic results of EUS for venous invasion evaluation demonstrated a sensitivity of 100%, specificity of 95.93%, PPV of 84.38%, NPV of 100%, and an accuracy of 96% compared to CT (Table 9).

Accuracy of EUS in arterial invasion
The diagnostic results of EUS for arterial invasion evaluation yielded a sensitivity of 95.65%, specificity of 100%, PPV of 100%, NPV of 99.44%, and an accuracy of 99.5% compared to CT (Table 10).

Discussion
Pancreatic cancer stands as one of the most formidable malignancies in terms of prognosis, characterized by a discouraging five-year survival rate that scarcely exceeds 10% in the USA [10].A small subset of patients is fortunate enough to be diagnosed with pancreatic cancer at an early stage, affording the possibility of radical surgical intervention.Nonetheless, even under such circumstances, the five-year survival rate struggles to surpass the 20% threshold [1].The accurate evaluation of the intricate relationship between tumors and blood vessels is of paramount importance for determining the resectability of pancreatic cancer and predicting its prognosis.While CECT is currently considered the "gold standard" for the primary assessment of pancreatic cancer, the application of this technique faces limitations.Not all patients can tolerate CT evaluation involving intravenous contrast due to factors such as allergic reactions or impaired kidney function [4].It is worth noting that approximately 0.6% of patients exhibit allergies to contrast medium.In this context, EUS is a valuable tool capable of rigorously evaluating pancreatic cancer and assessing vascular invasion without needing contrast agents [5][6][7][8][9][10][11].
Dahiya et al.'s nationwide survey in the USA from 2008 to 2017 highlighted a temporal gender shift in pancreatic cancer prevalence.While a slight female predominance was observed in 2008, a subsequent shift toward a slight male predominance was recorded in 2017 [12].Furthermore, Cai et al. emphasized that pancreatic cancer is predominantly an affliction of the elderly, with a median age at diagnosis of 70 years.Interestingly, the percentage of individuals diagnosed before age 55 is quite limited [13].The increasing number of hospitalizations among individuals aged 65-79 due to pancreatic cancer, as revealed by Dahiya et al., underscores the significance of age-related factors in the disease's epidemiology [12].The notion of agerelated telomere dysfunction, as explained by Matsuda, provides a potential rationale for the increased incidence of pancreatic cancer among the elderly [14].
Lugo et al.'s work offered insights into the relationship between smoking and pancreatic cancer risk, indicating a notable elevation in risk even with limited tobacco consumption.This observation reinforces our findings regarding the heightened risk associated with smoking [15].The clinical presentation of pancreatic cancer in our study predominantly manifested as obstructive jaundice (66%), followed by abdominal pain (22%).Gohar et al.'s study yielded slightly different results, where abdominal pain was the dominant complaint (75%), followed by obstructive jaundice (21.1%) [11].The divergences in clinical presentation may be attributed to the varying sample sizes between the studies.
Our study's observation of the head of the pancreas as the primary location for pancreatic cancer (92%) and the body as a less frequent site (8%) was corroborated by Gohar et al.'s findings [11].However, Fujii et al. reported a distinct distribution, with 54.4% of cases in the head and 31.5% in the body [5].Site distribution variability could stem from differing patient cohorts and geographic disparities.Moreover, while our study reported a tumor size of 35 (18-90) mm, Fujii et al. identified a smaller tumor size of 26 (18-33) mm [5].The prevalence of ductal adenocarcinoma as the most common histological type in our study (94%) aligned with Fujii et al.'s findings (92.1%) [5].
Discrepancies between our study and Gohar et al.'s research in terms of tumor grading were evident, where the proportions of patients in different grading categories varied [11].Regarding resectability, our study noted a resectable rate of 40%, whereas Gohar et al. recorded a resectable rate of 24% [11].These disparities underscore the multifaceted nature of pancreatic cancer diagnosis and evaluation.
Our study demonstrated the diagnostic prowess of EUS in assessing venous and arterial invasion in pancreatic cancer.The high sensitivity, specificity, PPV, NPV, and accuracy observed in our study's EUS evaluations mirrored the results of Fujii et al. [5].These findings highlight EUS as a reliable alternative to CT, particularly its ability to provide tissue samples and circumvent contrast agents. .

TABLE 9 : Accuracy of EUS in veins after correction of veins number
CT, computed tomography; EUS, endoscopic ultrasound; NPV, negative predictive value; PPV, positive predictive value