Correlation between positive biopsy rates and contrast-enhanced ultrasound findings in patients with pancreatic cancer: a retrospective analysis of percutaneous ultrasound-guided fine-needle aspiration

Introduction

Pancreatic cancer, one of the most malignant tumors of the digestive system and the fourth most lethal type of cancer in the United States, is associated with a 5-year survival rate of only 13% (1). The predominant characteristics of pancreatic cancer include early and frequent metastasis, as well as atypical early symptoms, which collectively contribute to the challenge of achieving an early diagnosis. The majority of patients are diagnosed at an advanced stage or with distant metastasis, precluding the possibility of radical surgery (2). Chemotherapy or neoadjuvant chemotherapy is the mainstay of treatment for these patients. A histological diagnosis should be obtained before chemotherapy for patients with unresectable pancreatic cancer. Due to the rapid progression of pancreatic cancer, fast and accurate pathological diagnosis is critical for improving patient prognosis. Imaging modalities, including transabdominal ultrasound, endoscopic ultrasonography (EUS), contrast-enhanced computed tomography (CT), contrast-enhanced ultrasound (CEUS), magnetic resonance imaging, magnetic resonance cholangiopancreatography, and endoscopic retrograde cholangiopancreatography, all play important roles in the diagnosis and staging of pancreatic cancer (3,4). Although EUS, contrast-enhanced EUS, and EUS-guided fine-needle aspiration (EUS-FNA) are reliable tools for diagnosing pancreatic cancer, they have certain limitations (5,6).

Compared to EUS-FNA, percutaneous ultrasound-guided fine needle aspiration (US-FNA) is less expensive, can be performed without deep sedation, and has minimal invasiveness. In the guidelines from the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) for interventional ultrasound (INVUS), percutaneous US-FNA is recommended for biopsy, especially in unresectable cases (7). CEUS, which includes the use of contrast agents to enhance the assessment of microvascular conditions, can improve the characterization of pancreatic lesions detected on ultrasound (8). It was also reported that CT combined with CEUS can achieve better results for the diagnosis of pancreatic cancer (9). Previous results have also indicated that CEUS before biopsy can increase the biopsy accuracy from 94.7% to 95.1% and raise the success rate of biopsies (10-12). Further in-depth research on the impact of perfusion characteristics identified in CEUS before biopsy procedures can further enhance the accuracy of punctures, reduce the need for repeat biopsies, and secure a longer period of treatment time for patients.

The aim of this study was to identify ultrasound and clinical factors related to the efficacy of percutaneous US-FNA and evaluate whether the perfusion characteristics identified in CEUS affect biopsy results. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2975/rc).

Methods

A retrospective comparative analysis was conducted to evaluate the clinical factors of patients with varying percutaneous US-FNA results and to assess the percutaneous US-FNA outcomes among patients with different CEUS findings. The primary objectives were to identify key factors influencing the efficacy of percutaneous US-FNA and to determine whether the perfusion characteristics observed in CEUS examinations impact the biopsy results.

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments, and was reviewed and approved by the Ethics Review Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (No. I-24PJ1009). Since the data were collected retrospectively and are fully anonymized, the requirement for individual consent was waived.

Patient population

Patients who underwent CEUS and percutaneous US-FNA at Peking Union Medical College Hospital and were finally diagnosed with pancreatic cancer clinically or pathologically from January 2018 to December 2023 were retrospectively enrolled in the study. The number of cases meeting the inclusion criteria during the study period determined the sample size. Comprehensive evaluations of pertinent information, encompassing clinical data, prebiopsy lesion imaging, and both immediate and delayed complications, were conducted through use of the patient record system. The inclusion criteria were (I) completion of both CEUS within 2 weeks before percutaneous US-FNA and (II) a pathological or clinical diagnosis of pancreatic cancer. Meanwhile, the exclusion criteria were as follows: (I) cystic-solid masses; (II) a diagnosis of adenosquamous carcinoma, neuroendocrine carcinoma, metastasis from other sites, and other non-adenocarcinoma malignant tumors; (III) incomplete relevant clinical information; and (IV) administration of chemotherapy or surgery between CEUS and biopsy. The sample size for this case-control study was calculated via the epi.sscc function in the epiR package of R version 4.2.1 (The R Foundation for Statistical Computing, Vienna, Austria).

CEUS procedure and image analysis

CEUS was performed within 2 weeks before the ultrasound-guided biopsy, and patients fasted for more than 8 hours prior to both of the examinations. The contrast agent used was SonoVue (Bracco, Milan, Italy). The suspension was prepared according to the manufacturer’s instructions. The CEUS procedure was performed with a iU22 or EPIQ 7 device (Philips, Amsterdam, the Netherlands) equipped with a C5-1 probe. Conventional ultrasound evaluated the size, position, shape, echogenicity, margin, and texture. and vascularity of the lesions. Contrast-enhanced imaging was then conducted. As a first injection, the suspension was administered in 2–3 seconds, and a second injection was performed as necessary. The dynamic images were recorded for more than 2 minutes.

Image analysis was independently completed by two senior radiologists (K.L. and Y.G., with more than 10 years of experience in ultrasound examinations in abdominal disease and CEUS). When inconsistent results occurred, a consensus was reached through discussion or consultation with a third radiologist. The kappa test was employed to evaluate the consistency of quality assurance measurements between observers. The enhancement and reduction patterns were observed during the analysis. The perfusion time was divided into the arterial phase (10–30 seconds) and the venous phase (30–120 seconds). The enhancement patterns were categorized based on their comparison with normal pancreatic tissue during arterial phase as hyperenhancement, isoenhancement, or hypoenhancement. According to the enhancement pattern, the patients were divided into a hyperperfusion group (the rich group) and a hypoperfusion group (the poor group). The rich grouped included the following: (I) patients that showed isoenhancement in the arterial phase (due to the biological characteristics of pancreatic cancer, none of the included patients exhibited significant hyperenhancement in the arterial phase); (II) patients that showed uneven enhancement, with the area of high enhancement or isoechoic enhancement exceeding 50%; (III) and patients with diffuse slightly hypoenhancement lesions in whom the tumor area was uniformly enhanced and the degree of enhancement during the arterial phase was slightly lower than that of the pancreatic parenchyma. The poor group included (I) patients that showed hypoenhancement in the arterial phase; and (II) patients that showed uneven enhancement with the area of hypoenhancement exceeding 50% (Figure 1). All lesions in our cohort demonstrated rapid washout during the venous phase.

Figure 1 Examples for the classification of contrast-enhanced ultrasound perfusion characteristics. (A,B) Patients showing hypoenhancement in the arterial phase were classified into the poor group. (C,D) Patients with diffuse slightly hypoenhanced lesions in whom the tumor area was uniformly enhanced and the degree of enhancement during the arterial phase was slightly lower than that of the pancreatic parenchyma were classified into rich group. (E) A patient with isoenhancement in the arterial phase who was assigned to the rich group. (F) A patient with uneven enhancement and an area of isoechoic enhancement exceeding 50% who was assigned to the rich group. Arrows represent areas of tumor. M, mass; P, pancreas.

US-FNA procedure

An initial baseline ultrasound was performed by experienced radiologists (K.L. and L.T.) for thorough evaluation of lesions. The size, position, and composition of the lesion were documented. Color Doppler imaging was used to identify blood vessels within and surrounding the lesion to determine the safest percutaneous approach. US-FNA was performed with a MyLab70 ultrasound unit (Esaote Biomedica, Genova, Italy) equipped with 20-gauge, 200-mm FNA needles (Hakko Co., Ltd., Chikuma, Japan). Prior to the procedure, the skin was prepared in a sterile manner, and local anesthesia (2% lidocaine) was administered. Under ultrasound guidance, a puncture needle was then inserted into the lesion. The patients were instructed to hold their breath to prevent injury. After reaching the inner leading edge of the target lesion, the needle was inserted and withdrawn from the target lesion around 15 to 30 times to obtain an adequate sample. The entire procedure was monitored with conventional ultrasound to ensure proper visualization of the needle tip. After the biopsy, the patients were monitored in an observation room for 2 hours, and a routine ultrasound examination was performed to exclude bleeding and other complications.

Cytologic analysis

The pathological diagnosis was completed according to the World Health Organization (WHO) reporting system for pancreaticobiliary cytopathology. The FNA diagnoses were classified into six categories: (I) nondiagnostic; (II) negative for malignancy; (III) atypical; (IV) neoplastic (premalignant or low-grade malignant); (V) suspicious for malignancy; and (VI) positive for malignancy. Among the cases we enrolled, none met the nondiagnostic category. To facilitate the analysis, we categorized the remaining diagnoses into three groups as follows: (I) negative for malignancy was considered to be negative; (II) atypical, neoplastic, and suspicious for malignancy were considered to be suspicious; and (III) positive for malignancy was considered to be positive.

Statistical analysis

All data were processed with the R software version 4.2.1. The criterion of statistical significance was set as a P value <0.05 or an adjusted P value <0.05. The parametric test of the Student t-test and the nonparametric test of the Mann-Whitney test were performed to compare the differences between the two groups. For nonparametric comparisons of three independent groups, the Kruskal-Wallis H test is used. The adjusted P value was calculated via Benjamini-Hochberg correction, and the chi-squared test was used to analyze the categorical variables. Univariate and multivariate logistic regression analyses were carried out with R’s default glm() command (R version 4.2.1). A positive FNA result was defined as the positive event.

Results

Figure 2 shows the enrollment of the final study population. A total of 814 patients who underwent percutaneous US-guided puncture for pancreatic lesions from January 2018 to December 2023 were identified. Among them, 576 underwent percutaneous US-FNA, and 548 underwent CEUS before the biopsy. A total of 184 cases were excluded. The reasons for exclusion were a confirmed diagnosis of pathological types other than ductal adenocarcinoma or loss to follow-up resulting in no definitive diagnosis. A total of 364 patients with clinically or pathologically confirmed pancreatic cancer were included, and after 58 patients with cystic disease were excluded, a final cohort of 306 solid cases was obtained.

Figure 2 Flowchart patient enrollment (by FigDraw). CEUS, contrast-enhanced ultrasound; GIST, gastrointestinal stromal tumor; IPMN, intrapancreatic mucinous neoplasm; MCN, mucinous cystic neoplasm; NEC, neuroendocrine carcinoma; p-NET, pancreatic neuroendocrine tumor; PUMCH, Peking Union Medical College Hospital; SPN, solid pseudopapillary neoplasm; US-FNA, ultrasound-guided fine needle aspiration.

The baseline characteristics of the patients are shown in Table 1. The final study sample consisted of 306 patients (155 males and 151 females), with individuals aged 60 years and older accounting for 60.78% (186/306). Among them, 191 (62%) had positive biopsy results, 86 (28%) were classified as suspicious, and 29 (9.5%) had negative results. There were no statistical differences between the three groups (positive, negative, and suspicious) in terms of age, gender, tumor size, tumor location, or carbohydrate antigen 19-9 (CA19-9) levels. Notably, the median CA19-9 levels incrementally increased from negative to suspicious to positive patients, ranging from 127 to 235 U/mL, although this result was not statistically significant.

For the evaluation of CEUS characteristics, a kappa value of 0.958 indicated good agreement between observers. Among the final 306 patients included, those placed in the poor group accounted for 61% (186/306), while those in the rich group accounted for 39% (120/306). There were no statistically significant differences between the two groups in terms of gender, age, tumor size, tumor location, or CA19-9 levels (Table 2). Since there was no statistically significant difference in baseline characteristics between the two groups, subsequent statistical analyses did not include stratified analyses for confounders such as age and tumor location. As shown in Table 3, the proportion of patients with negative biopsy results in the rich group (15.8%) was significantly higher than that in the poor group (5.4%), and the proportion of patients diagnosed as positive was lower (51.7% vs. 69.4%) (P=0.001). Univariate and multivariate regression analyses were performed to identify risk factors associated with the puncture result, as summarized in Table 4. The CEUS characteristics remained a significant independent risk factor for the diagnostic yield of percutaneous US-FNA, with an adjusted odds ratio (OR) of 0.472 [95% confidence interval (CI): 0.291–0.760; P<0.05]. Through a retrospective analysis of pathological images from multiple cases, it was observed that samples from the poor group exhibited more intact tissue structures as compared to those from the rich group, thereby providing enhanced diagnostic information (Figure 3).

Figure 3 Comparison of CEUS features and pathological pictures from biopsy in patients with different perfusion characteristics. (A,B) CEUS image and pathological picture from a 70-year-old male with PDAC in the rich group. (C,D) CEUS image and pathological picture from a 70-year-old female with PDAC in the poor group. (B) Hematoxylin and eosin staining, ×40; (D) hematoxylin and eosin staining, ×20. Arrows represent areas of tumor. CEUS, contrast-enhanced ultrasound; M, mass; P, pancreas; PDAC, pancreatic ductal adenocarcinoma.

Among the patients included, 16 underwent EUS-FNA. Among the patients with negative findings in EUS-guided FNA, two subsequently had positive results from percutaneous US-FNA, two cases had suspicious malignancy results, and one case remained negative. Two of the patients received positive results both in EUS-FNA and percutaneous US-FNA. Upon analyzing their CEUS images, we found that patients with two negative punctures in both EUS-FNA and percutaneous US-FNA exhibited isoenhancement (Figure 4A,4B), while those with two positive punctures were classified into the poor group (Figure 4C,4D).

Figure 4 CEUS images of percutaneous US and gray-scale images of EUS in patients with both EUS-FNA and percutaneous US-FNA results. (A,B) A CEUS image of percutaneous US and the gray-scale image of EUS in a male patient with PDAC with a negative biopsy result in both EUS-FNA and percutaneous US-FNA. (C,D) CEUS image of percutaneous US and the gray-scale image of EUS in a female patient with PDAC with positive biopsy results in both EUS-FNA and percutaneous US-FNA. Arrows represent areas of tumor. CEUS, contrast-enhanced ultrasound; EUS, endoscopic ultrasonography; EUS-FNA, endoscopic ultrasonography-guided fine needle aspiration; HA, hepatic artery; M, mass; P, pancreas; PDAC, pancreatic ductal adenocarcinoma; SPA, splenic artery; US-FNA, ultrasound-guided fine needle aspiration.

Discussion

Through the results of this study, we found that percutaneous US-FNA can provide diagnostic information for over 90% of cases, with diagnostic efficacy similar to that of EUS-FNA (88.9%) and comparable to that of core needle biopsy (CNB) (91–100%) (13-15). This result supports cytological aspiration as a viable option in the diagnosis of pancreatic cancer. This study also investigated the differences in the positivity rates from percutaneous ultrasound-guided pancreatic biopsy among patients with different CEUS enhancement characteristics. Overall, patients in the rich group had a lower positivity rate from biopsy.

CEUS, by reflecting microcirculation characteristics, can indicate the presence of a tumor microenvironment and microvascular perfusion. Research across various tumor types has attested to the correlation between quantitative CEUS findings and microvessel density (MVD) (16-18). The EFSUMB stated that CEUS can improve the accuracy of percutaneous ultrasound-guided pancreatic procedures (19). Compared to gray-scale ultrasound and color Doppler, CEUS can better reflect the microcirculatory characteristics of pancreatic tumors and thus occupies an important position in the diagnosis and differential diagnosis of pancreatic cancer (8,19). Furthermore, during US-FNA, CEUS assists in differentiating tumor tissue from perilesional inflammation and in defining tumor margins (20). It also facilitates the planning of an optimal puncture path, which involves identifying and avoiding critical structures such as necrotic regions and major blood vessels. Nevertheless, the diagnostic efficacy of FNA for pancreatic lesions, even when assisted by CEUS, remains subject to further enhancement. This may necessitate repeated punctures, thereby impacting the accuracy of definitive diagnoses and subsequent treatment plans for patients. The false-negative results of the puncture may be related to the characteristics of the tumor itself. In clinical practice, it has been observed that the vascularization of pancreatic tumors can influence the outcomes of biopsy procedures, and this observation prompted the initiation of the present study. The findings of our study suggest that pancreatic lesions characterized by a poor blood supply are more likely to yield positive biopsy results.

It was previously assumed that regions with abundant blood supply within tumors contain a higher density of tumor tissue and more active tumor proliferation, thereby facilitating positive biopsy outcomes. In contrast, areas with limited blood supply were thought to contain a greater proportion of necrotic tissue, resulting in false-negative biopsy results. However, we found that the incidence of positive biopsies was, in fact, elevated in tumors categorized within the poor group. This divergence from previously established notions presents an intriguing area for further investigation. This contradiction can be partially ascribed to the inherent biological characteristics of pancreatic cancer. Previous research has shown that pancreatic cancer typically presents as hypovascular (8,21,22). The desmoplastic reaction is a critical feature of the tumor microenvironment in pancreatic cancer, with extensive fibrosis potentially contributing to an inadequate blood supply, resulting in hypoenhancing characteristics in contrast-enhanced CT and CEUS (23-25). Therefore, areas with poor CEUS enhancement may represent typical tumor regions rather than necrotic tissue. Moreover, during the research process, we also found that the FNA samples obtained from the poor group exhibited more complete structural characteristics. During FNA puncture, tissues are repeatedly incised and aspirated into the needle under negative pressure. For tumors in the poor group, the presence of abundant stroma facilitated the acquisition of sufficient and relatively intact samples. Conversely, lesions characterized by a relatively rich blood supply may undergo hemorrhage due to the incision of small blood vessels, thereby complicating the accurate assessment of the effective components within the aspirated specimens.

The findings indicate that obtaining sufficient samples during pancreatic biopsies on highly vascularized lesions is essential. A rapid bedside evaluation can ascertain the sufficiency of the sample volume, and when feasible, employing histological CNB techniques can improve the procedure’s success rate, minimizing the necessity for repeat biopsies. Consequently, it is imperative to evaluate the vascularity of the tumor prior to puncture. Besides providing diagnostic information, CEUS also significantly aids in guiding the puncture procedure. Although our study was primarily based on percutaneous US-FNA, the findings are equally applicable to EUS-FNA.

Reported complications of ultrasound-guided percutaneous pancreatic lesion biopsy included cardiovascular/cerebrovascular accidents, hemorrhage, pancreatitis, peritonitis, abdominal pain, and needle tract seeding. These adverse events are primarily attributed to CNB (13); however, no complications were observed in this study, which can be attributed to three key factors: the exclusive use of US-FNA for all procedures; preoperative needle trajectory planning under ultrasound and CEUS guidance to circumvent vasculature, particularly venous dilatations secondary to pancreatic portal hypertension; and vigilant postoperative patient monitoring. Compared to US-FNA, CNB better preserves tissue architecture, enabling more accurate histological diagnosis and advanced pathological analysis (26). However, it entails a higher risk of complications (27). In pancreatic cancer, the presence of pancreatic portal hypertension necessitates preprocedural evaluation of the peritumoral vascular anatomy before percutaneous puncture. The operator must carefully plan the needle trajectory to avoid traversing the dilated venous collaterals, thereby minimizing the risk of intraprocedural bleeding and other complications. Furthermore, the use of an FNA needle, as opposed to a cutting needle such as a core needle, helps prevent vascular injury and reduces the potential for significant hemorrhage. Moreover, for pancreatic cancer, a tumor characterized by low cellularity, US-FNA demonstrates comparable diagnostic efficacy to that of CNB, especially when supported by experienced cytopathologists (26). The excellent safety profile observed in our study aligns with a previous work in which a 20-gauge needle provided sufficient tissue for cytopathological evaluation while maintaining a low complication rate (13). Therefore, our strategy emphasizes the use of CEUS to screen patients: CNB should be considered for tumors showing rich enhancement when technically feasible to optimize yield; however, for the other cases, FNA provides equivalent diagnostic utility with a reduced overall complication risk.

This study involved several limitations that should be acknowledged. To begin, as a single-center retrospective analysis, it was constrained by a limited sample size. Second, the exclusion of biopsy-negative patients lost to follow-up might have led to an underestimation of the false-negative rate. Furthermore, although we implemented a standardized review process involving two independent readers with arbitration provided by a senior expert in cases of disagreement and demonstrated good interobserver agreement through kappa analysis, the interpretation still requires considerable expertise. In addition, our proposed classification criteria are based primarily on qualitative, morphological descriptions rather than objective, continuous quantitative parameters, such as time-intensity curve analysis. This may affect the precision and reproducibility of the classification system. Therefore, the clinical relevance and applicability of the proposed classification framework should be further investigated and validated in larger, multicenter studies. Future work should also focus on developing more standardized criteria that integrate both qualitative observations and quantitative metrics.

Beyond our main findings, several details warrant brief mention. First, regarding the exclusion criteria, we excluded cystic-solid lesions to ensure cohort homogeneity. Their complex architecture confounds the interpretation of key CEUS parameters (e.g., enhancement and filling), and their required puncture technique differs from that for solid masses. Second, although Table 1 indicates a rise = in CA19-9 levels from negative to positive cases, this observation did not reach statistical significance. This may be attributed to the intrinsic limitations of CA19-9 measurement. Although CA19-9 is the only US Food and Drug Administration-approved serum biomarker for pancreatic cancer, its utility is still limited by its moderate diagnostic accuracy (sensitivity 80%, 95% CI: 72–86%; specificity 75%, 95% CI: 68–80%) (28). Furthermore, CA19-9 levels can be influenced by conditions such as inflammation and biliary obstruction (29,30). Additionally, false-negative results may occur in Lewis antigen-negative individuals (31). Overall, our findings suggest that percutaneous US-FNA is a safe and effective technique for obtaining pathological samples in cases of pancreatic cancer, demonstrating a wide range of applicability. The blood supply characteristics indicated by CEUS are correlated with the positive rate of biopsy. For patients exhibiting a rich blood supply, increasing the sampling volume or utilizing histological CNB may enhance diagnostic efficacy, expedite the diagnostic process, and ultimately offer patients greater opportunities for treatment.

Conclusions

This study demonstrated that the microvascular perfusion characteristics of pancreatic lesions evaluated with preprocedural CEUS are significantly correlated with the diagnostic yield of percutaneous US-FNA. Specifically, lesions with poor blood supply, as suggested by CEUS, demonstrated a significantly higher positive biopsy rate. For lesions classified in the rich group, which shows a higher likelihood of nondiagnostic or negative results, optimizing the biopsy strategy is recommended to improve diagnostic efficacy. These findings underscore the value of CEUS both as a diagnostic tool and a prebiopsy planning modality, which can facilitate a more personalized and effective approach to obtaining pathological confirmation in patients with pancreatic cancer and thus ultimately optimize the clinical management of these patients.

Acknowledgments

Thanks to Dr. Jie Cai for the guidance in statistics.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2975/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2975/dss

Funding: This study was supported by the National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-D-001) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS) (No. 2023-I2M-C&T-A-005).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2024-2975/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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was reviewed and approved by the Ethics Review Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences (No. I-24PJ1009). Since the data were collected retrospectively and are fully anonymized, individual consent was waived.

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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