A retrospective study was carried out to review 191 cases of EUS-FNAC of pancreatic lesions between January 2010 and December 2012 in Seoul National University Hospital. This study was approved by the Seoul National University Hospital Institutional Review Board (IRB Study No. H-1408-022-601).

EUS-FNAC for pancreatic solid tumor is widely performed and has been shown to be useful [3,5,7,8]. As EUS-FNAC has gained acknowledgement as the gold standard for obtaining patient specimens, the importance and demand for optimization of EUS-FNAC increase. We, given the relatively large number of cases of pancreatic FNAC in South Korea, have recognized that follow up and review are needed of past EUS-FNAC results in order to determine the validity of the examination process. The aim of the current study was to contribute to the advancement of management for pancreatic cancer patients by improving the detection and diagnosis results.

To analyze the accuracy, we investigated the diagnosis of EUS-FNAC by comparing with final diagnoses confirmed by histological examination of biopsy or surgically resected specimens. During evaluation of the diagnoses made by EUS-FNAC, we emphasized the agreement with the final diagnoses.

In our data, 61.7% of cases were true-positive and 16.8% of cases were true-negative, with false-negative and false-positive cases comprising only 21.6%, which is acceptably low considering that most were due to adequacy problems with the EUS-FNAC specimen. As a result, diagnostic accuracy, sensitivity, and specificity were 78.4%, 79.2%, and 75.7% respectively. The positive predictive value was 92.0%, and negative predictive value was 50.9%. The false-positive rate was 24.3%, false-negative rate was 11.6%, and false discovery rate was 8.0%. According to Yoshinaga et al. [5], a medical literature review to evaluate the role of EUS-FNAC for diagnosis of solid pancreatic masses showed 78%–95% sensitivity, 75%–100% specificity, 98%–100% positive predictive value, 46%–80% negative predictive value, and 78%–95% accuracy. In comparison of this data with data from several other studies [9-12], our study showed lower but within the range values of diagnostic accuracy, sensitivity and specificity. The positive predictive value was 12% higher than the upper margin, but the negative predictive value was lower than the mean. Our overall results were affirmative and supportive of the continued use of EUS-FNAC for pancreatic lesion, but it is apparently lower than other institutes. This encourages us to look for an explanation and identify mechanisms for improvement. Such relatively poor result may be due to the way of manipulating raw data during patient selection and categorization of diagnoses. By adjusting our methods to be more identical to those of other studies, we may have gained more satisfying results, similar to those of other institutes.

After confirming that the overall results were comparatively favorable in our study, we focused on the cases that showed discrepancy in order to identify the pitfalls of diagnosis and further improve the cytologic diagnosis. We reviewed the slides and analyzed the diagnoses of 35 cases in which the cytologic diagnosis did not concur with the surgical diagnosis. Among those cases, 12 were due to insufficient aspiration of cells for diagnosis (category 1), and 16 were due to targeting error (category 2), containing only benign parenchyma instead of tumor. The remaining 7 discrepant cases (category 3) were due to misinterpretation and misdiagnosis by pathologists.

Categories 1 and 2 results indicate aspiration failures caused by technical variables, such as operator skills/experiences, tumor type and location. With regard to location, cases were aspirated most often from the body (11 cases), followed by head (5 cases) and tail (4 cases). The interpretation is that the aspirations from these regions have a tendency to be insufficient due to poor accessibility and technical difficulty. However, it could just be a matter of fraction, representing the most common location of the suspected tumor in this study population. The most common cytologic diagnosis for categories 1 and 2 was ‘adenocarcinoma’ (19 cases), followed by ‘negative for tumor’ (5 cases), neuroendocrine tumor (1 case), intraductal papillary neoplasm (1 case), and 1 case of ‘malignancy, unspecified.’ Considering that adenocarcinoma was the most common diagnosis overall (adequate/inadequate, discrepant/non-discrepant), tumor type may have less impact on aspiration failure. In addition, we took into consideration that cases of intraductal papillary mucinous neoplasm may have been underdiagnosed as ‘benign lesion’ in this study. Therefore, we concluded that the relativity of tumor type and diagnostic accuracy is still ambiguous. Also, we assumed that there are significant influences from variability in operator skills and tumor size on EUS-FNAC results. However, we could not analyze such data because the electric medical records did not document the specific operator’s name and tumor size in all cases.

For category 3, the misdiagnosed cases, we reviewed the slides to identify the factor that led to such discrepancy. Of 7 cases, four were histologically adenocarcinoma but cytologically diagnosed negative. Meticulous observation led to identification of some obviously malignant cells that resemble adenocarcinoma in 3 cases (cases Nos. 31–34) (Table 4, Fig. 1A). In these cases, we think the misdiagnosis was due to screening failure and simple exclusion of the applicable areas on the slide. On the other hand, one histologically adenocarcinoma but cytologically diagnosed ‘negative’ case was actually challenging (case No. 32) (Table 4, Fig. 1B, C). As reviewers retrospectively observing the collection of ‘discrepant’ cases only, it was not difficult to interpret this case as malignant since we knew that something must be wrong. However, tumor cells in this case were intermixed with and camouflaged by a massive amount of benign parenchymal cells, making the malignancy ambiguous. In a situation like this, a pathologist may be discouraged and hesitant to conclude a diagnosis of definite cancer.

Intraductal papillary mucinous neoplasm was misdiagnosed as negative in 1 case (case No. 35) (Table 4, Fig. 1D). From review of the slide, we recognized some mucin-producing epithelial cells with suspicious atypism. We assumed that the discrepancy in this case was due to diagnosis by a relatively inexperienced pathologist, leading to misinterpretation.

There were 3 cases surgically diagnosed as ‘consistent with lymphoplasmacytic sclerosing pancreatitis.’ Among them, 2 cases were cytologically misdiagnosed as ‘atypical,’ resulting in discrepancy (cases Nos. 29 and 30) (Table 4). The remaining case was cytologically diagnosed ‘negative for tumor’ and was categorized as a true negative result. Lymphoplasmacytic sclerosing pancreatitis, a form of chronic pancreatitis with mixed inflammatory infiltrate, clinically mimics pancreatic cancer. Preoperative detection is important because lymphoplasmacytic sclerosing pancreatitis patients usually respond to steroid therapy with reversible improvement in pancreatic morphology and function [13]. In our cases, inflammatory infiltrate consisting mainly of lymphocytes and plasma cells was observed. According to Abraham et al. [14], this infiltrate may also contain some macrophages and occasionally neutrophilic and eosinophilic granulocytes. Although the role of FNAC is mainly to distinguish malignant from benign cells, it is worth considering the possibility of lymphoplasmacytic sclerosing pancreatitis when investigators recognize such microscopic features because patients will benefit from earlier initiation of therapy.

We also reviewed a case of schwannoma that was cytologically diagnosed as ‘a few atypical cells’ (Fig. 2). Cytopathologic features presented mostly in tissue fragments or in fascicles, with cells fusiform and elongated with poorly defined cell borders. The cells showed a low nuclear-cytoplasmic ratio with long and wavy nuclei. Nucleoli were inconspicuous, and cytoplasm was pale. Pancreatic schwannoma is an extremely rare neoplasm, with only 47 cases reported in the English literature in the last three decades [15]. Therefore, it is not routine for pathologists to suspect such schwannoma when screening. However, the possibility that cells are mesenchymal should be considered, which may suggest the diagnosis.

Navina et al. [16] and Kim et al. [6] reported that absence of an immediate on-site cytopathologist is not critical, and they found no association with on-site evaluation and specimen cellularity. However, many groups, for example, Fisher et al. [8], have reported that on-site evaluation was relatively accurate (77.5%) and highly specific for malignancy (100%), significantly contributing to the efficiency and accuracy of the procedures. With respect to our lower diagnostic accuracy in comparison to those of other institutes, absence of on-site evaluation may be the cause because 28 of 35 discrepant cases in our study were due to unsatisfactory specimens. We presume that we could have benefited from on-site evaluation to improve diagnostic results and reduce the number of discrepant cases. In our opinion, having immediate on-site evaluation would be beneficial and valuable, if circumstances allowed.

The design of this study was limited by the fact that it was a single-center retrospective review of a relatively small number of consecutive cases over a 36-month period. Thorough adequacy assessment of pancreatic EUS-FNAC was impossible since only one representative specimen of patients with multiple aspirations was analyzed. Had we not excluded numerous ‘IFD’ cases, there would have been a greater amount of useful data, which would have reduced the impact of incorrect results caused by technical difficulty. Also, data identifying the operator and pathologist should have been retrieved to analyze artificial error that depends on skill and experience. Further study on cases with discrepancy aimed to identify the pitfalls of diagnosis should involve more cases of misdiagnosis, increasing the power of the analysis. Awareness of such pitfalls is important because it increases diagnostic confidence, resulting in improved accuracy.

In summary, the diagnostic accuracy of EUS-FNAC for obtaining pancreatic specimens suspicious of malignancy was confirmed to be high in this study. Diagnostic accuracy, sensitivity, and specificity were 78.4%, 79.2%, and 75.7% respectively. Although 35 of 191 cases showed discrepancy in cytology-histology diagnosis, most were due to insufficient aspiration or mistargeted aspiration of cells, both of which preclude proper examination. Therefore, we conclude that EUS-FNAC is reliable and accurate. Based on these results, pathologists can be assured of their diagnosis, as EUS-FNAC provides a desirable representation of the specimen. However, particular attention to adequacy assessment and meticulous observation of samples are critical in order to reduce the discrepancy between cytologyhistological diagnoses. Though the percentage of correct diagnoses in EUS-FNAC results is relatively inferior compared to that from histological diagnosis, statistical results, such as diagnostic accuracy, were satisfactory in several studies including ours. Therefore, EUS-FNAC can be encouraged as a first-line pathologic examination for pancreatic lesion with high clinical suspicion of malignancy when patient safety and financial benefits are the priority.