There is a paucity of literature defining specific EUS characteristics differentiating pancreatic adenocarcinoma from NPPA. Our findings suggest that patients with a diagnosis of adenocarcinoma were more likely to have lesions located in the pancreatic head, have vascular involvement, malignant-appearing lymphadenopathy, and PD and CBD dilation. This has been supported by other recent studies (11
). The mean number of FNA passes performed for adequate diagnostic cytopathology of pancreatic lesions in our series was four (range one to seven), which is within the range of previously reported studies (three to seven) (16
). PD and CBD dilation were more frequently present in our patients with adenocarcinoma. This can be attributed to the fact adenocarcinomas originate from the intraductal and acinar cells (18
). Based on univariate analysis, Rodriguez et al (7
) found that PD and CBD dilation were also significant findings predictive of cancer.
Additionally, the mean size of the lesions was not significantly different between the two groups. A retrospective study of 1000 cases (20
) revealed that EUS-FNA was more accurate than percutaneous FNA techniques for masses <3 cm in size and that computed tomography and transabdominal ultrasound may not reliably detect pancreatic tumours <3 cm in size. The reason to emphasize this is that a cut-off point of 3 cm is one of the variables shown to be a predictor of better outcome in patients with pancreatic cancer (21
). Among our patients, 26.6% with adenocarcinoma had lesions <3 cm in size. In these particular cases, early detection enables one to direct the clinical management of the patients and hopefully improve outcomes. Furthermore, larger lesions (ie, >5.0 cm) were more likely to be NPPA.
We excluded purely cystic lesions such as serous cystadenomas, simple cysts, lymphoepithelial cysts or pseudocysts. These are less likely to harbour an underlying malignancy than a solid or mixed solid/cystic-appearing lesion on EUS. Additionally, due to the increasing risk of infection with every subsequent pass, usually only one FNA is performed for evaluating purely cystic lesions. Cytology yield is generally low for cystic lesions. Therefore, surgical resection to determine true pathology is inevitable when a malignant pancreatic neoplasm cannot be entirely excluded (20
Some authors have argued that a tissue diagnosis is unnecessary in patients with a sufficiently high clinical suspicion for cancer and, as such, the course of action should be surgical resection (23
). We believe that the first step in management of the lesion is identification via FNA diagnosis. The lesions that yield a negative FNA can be further characterized by endosonographic features typical for adenocarcinoma versus NPPA lesions. This becomes particularly relevant in cases of NPPA, in which management is very different than in pancreatic cancer. For instance, patients with metastatic cancer to the pancreas have a very different approach to treatment, without any role for surgery, except for palliation. It our particular series, metastatic lesions accounted for 21% of the rare, atypical lesions.
The strength of our study was its unique approach to investigating EUS characteristics of solid and solid/cystic neoplasms as another method for diagnosis to be used with EUS-FNA. Imaoka et al (24
) reviewed a large-centre experience examining the utility of EUS-FNA and the prevalence of adenocarcinoma versus rare atypical lesions. They had 28 cases of rare (nonductal adenocarcinoma) pancreatic lesions. Of these, only 13 of 28 were defined malignant lesions (ie, pancreatic endocrine neoplasms, invasive intraductal papillary mucinous neoplasms), acinar cell canrcinoma, metastatic tumours and undifferentiated carcinoma with osteoclast-like giant cells); the other 15 were benign lesions. In our study, we reported 48 NPPA consisting of malignant solid and mixed solid/cystic pancreas lesions. According to our defined exclusion criteria, we would have eliminated the benign cases in their patient cohort. Nevertheless, their important study demonstrated that pancreatic neoplasms, other than ductal adenocarcinomas, have diverse imaging and histopathological features. In the study analysis by Imaoka et al (24
), EUS-FNA correctly diagnosed the type of neoplasm in 19 cases (67.9%) and distinguished between benign and malignant rare (‘nonductal adenocarcinoma’) tumours with a sensitivity of 69.2%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 79.0% and an overall accuracy of 85.7%. Similar to our study, this suggests that EUS-FNS is accurate in distinguishing features of pancreas neoplasms. Therefore, this supports our assertion that EUS-FNA may assist to establish a diagnosis of NPPA.
Limitations of our study include its retrospective trial design. It was also a single-centre trial with a limited sample size. Given the fact that we are a tertiary care and oncology referral centre, there may be a component of selection bias accounting for the high number (ie, 26%) of NPPAs. Most patients at our centre are referred by open-access endoscopy for EUS based on review of imaging studies and referral indications from their primary care physicians, or referring gastroenterologists, medical and surgical oncologists. Moreover, the present study was based on EUS-FNA findings, and we did not compare clinical presentation of symptoms between the two groups at the time of presentation. However, the strength of our trial is that there are limited data in the literature comparing the radiographic characteristics of atypical and typical pancreatic lesions. The information that we gained regarding the characteristics of adenocarcinoma appearance per EUS corroborates with existing literature and autopsy reports as elaborated above.
When EUS-FNA provides tissue that indicates malignancy, the positive predictive value is reported to be nearly 100% (25
). The negative predictive value of EUS-FNA can be relatively low, ranging from 16% to 85% (1
). A negative FNA cannot definitively rule out the presence of malignant disease. As many as one in 10 EUS-FNAs result in false-negative cytology (6
). This is where the findings of our study can truly be used. Patients with features of having a lesion in the head of the pancreas, ductal dilation, as well as lymphatic and vascular involvement, are more likely to have an adenocarcinoma (6
). At the same time, patients lacking these characteristics are more likely to have NPPA lesions, either benign or malignant, which may require a different management approach.
Nevertheless, FNA likely assists in the diagnosis of NPPA. As stated earlier in the Methods section, for the purposes of comparing FNA passes and diagnostic yield in patients with primary pancreas adenocarcinoma versus NPPA, we restricted the study cohort to patients who had an FNA diagnosis that was definitively positive or suspicious for malignancy. In an earlier article from our institution by Spier et al (6
), which investigated predictors of malignancy in the setting of a negative EUS-FNA, 17 of 55 patients (31%) with an initial negative/nondiagnostic FNA were subsequently diagnosed with pancreatic adenocarcinoma, with a mean time to diagnosis of 66 days from the initial false-negative FNA. However, in this group, none of these patients were diagnosed with other NPPAs. The true-negative FNA patients were followed for a mean of 403 days without the development of pancreatic malignancy. However, in this study, the patients who initially had a negative or nondiagnostic FNA, but were subsequently diagnosed with pancreatic malignancy, had a significantly increased risk of cancer in the setting of lymphadenopathy (P<0.001) and suspected vascular invasion/involvement (P<0.001). Therefore, these serve as strong positive predictors for adenocarcinoma. This was also reflected in the current study.
In this light, a recent study by Turner et al (29
) evaluated the accuracy of EUS-FNA in the diagnosis of pancreatic neoplasia. EUS-FNA was found to be 80% accurate for the detection of pancreatic adenocarcinoma using aspiration cytology. However, reclassification of suspicious cytology samples as diagnostic of malignancy resulted in a sensitivity of 93% for adenocarcinomas and 80% for pancreatic neuroendocrine tumours, with an overall improved accuracy rate of 94% (29
). In our retrospective cohort, initial EUS-FNA made the diagnosis of adenocarcinoma or NPPA in 90% of cases given strict cytological criteria, thus reflecting a very good accuracy rate. In approximately 11% of these cases (21 of 192 patients) that were interpreted as ‘suspicious’ for malignancy, 11 had confirmed NPPA based on repeat EUS-FNA, EUS-guided core biopsy or definitive pathology based on a surgical resection specimen.
Pancreatic mass lesions and tissue characterization may also be improved by the newer generation of endosonographic processers that use elastography. A recent study by Itokawa et al (30
) demonstrated that EUS elastography with semiquantitative analysis using the strain ratio was helpful in differentiating various mass lesions of the pancreas. In their retrospective analysis of 109 patients, they were able to accurately distinguish between mass-forming pancreatitis versus pancreatic cancer. However, a study by Hirch et al (31
) noted that the main limitation of EUS elastography in evaluating mass lesions of the pancreas was incomplete delineation of the border of lesions ≥35 mm in diameter or lesions at some distance from the transducer. They also noted that eleastographic recordings were hampered by the fact that the surrounding tissue was inadequately displayed in the larger mass lesions and this would impact on the strain ratio calculation. In this prospective study of 70 patients, they found that EUS elastography predicted the nature of pancreatic lesions with poor diagnostic sensitivity (41%), specificity (53%) and accuracy (45%). As a result, the authors concluded that the clinical utility of this technique remains questionable and it seems that the information provided would unlikely obviate the need for obtaining tissue samples via FNA for confirmation of a final pathological diagnosis.
Our study is one of the first to describe endosonographic features in addition to FNA cytopathology as a way to improve the accuracy of EUS and better characterize the findings as applicable to other NPPA lesions. The implications of the present study are that EUS-FNA may help in delineating the nature of pancreatic lesions and, therefore, may help in management. Moreover, among the NPPA lesions, there are a variety of lesions in which the treatment differs considerably for the individual subtype within the group (ie, lymphoma versus squamous cell carcinoma). Through our study, we hope to encourage other large tertiary multicentre studies to compare EUS features with FNA cytopathological analysis.
- EUS-FNA features can help distinguish malignant pancreas neoplasms including differentiating between primary adenocarcinoma and NPPA lesions.
- EUS characterestics that accurately help to diagnose primary pancreas adenocarcinoma include location of the mass lesion in the head of the pancreas, the presence of vascular invasion, malignant lymphadenopathy, PD dilation and CBD dilation. Lesions located in the tail of the pancreas, larger size lesions (ie, >5 cm) and lesions that require more than three FNA passes to establish a diagnosis are more often NPPA.
- In our study, 25% of malignant pancreatic neoplasms were NPPA, suggesting that EUS-FNA is essential in establishing a diagnosis and may be helpful in clinical decision making.