Multiple previous studies (1
) that examined the NPV of EUS-directed FNA for pancreatic lesions have been performed with varied results, but all have at least suggested that a negative FNA cannot effectively rule out pancreatic malignancy. Agarwal et al (1
) retrospectively evaluated 81 patients with EUS-FNA who were referred for clinical suspicion of pancreatic cancer and found EUS-FNA to have a 56% NPV that increased to 78% if patients had no definite mass lesions on spiral CT. Raut et al (8
) limited their analysis to patients with low-density masses in the pancreas on CT images or a malignant biliary stricture on percutaneous cholangiopancreatography or ERCP, and reported an NPV of only 44%. Eloubeidi et al (13
) prospectively evaluated 101 patients with suspected pancreatic neoplasm based on clinical and/or imaging studies, but included only solid pancreatic mass lesions in patients who had failed to obtain a tissue diagnosis by ERCP, CT-guided biopsy, and/or ultrasound-guided biopsy. Using these criteria, this group reported an NPV of 85% and stated that EUS-FNA can be used as a rescue modality when other techniques fail to obtain a diagnosis.
Varadarajulu et al (24
) evaluated the role of chronic pancreatitis in EUS-FNA of pancreatic lesions. They reported the significant reduction in sensitivity of a procedure to detect the presence of cancer when there was coexistent, chronic pancreatitis, and that significantly more EUS-FNA needle passes were required to establish a diagnosis compared with those without chronic pancreatitis. Subjects with benign lesions (final diagnosis) were more likely to have concomitant chronic pancreatitis compared with those who had adenocarcinomas.
Thus, EUS-FNA as used in the diagnosis of malignant pancreatic lesions, is not a perfect test with a not insignificant number of false-negative EUS-FNA results. This creates a clinical problem regarding the appropriate further management of these patients with suspicious lesions on previous pancreatic imaging or a clinical scenario suggestive of pancreatic malignancy, but negative EUS-FNA. Previous studies have not examined what measures should be taken with a patient in whom a risk of pancreatic malignancy remains even after negative FNA. The goal of the present study was therefore twofold. The first goal was to identify EUS imaging characteristics that could predict malignancy even when the FNA was negative or nondiagnostic. Given that no previous study had provided long-term follow-up of negative pancreatic EUS-FNA cases, the second goal was to determine a reasonable follow-up plan when the FNA of a pancreatic lesion is diagnosed negative.
With regard to EUS imaging, our results show that the findings of peripancreatic lymph nodes (P<0.001) and suspicion (on EUS) of vascular invasion by the pancreatic lesion (P=0.001) determined at the time of EUS, are statistically significant predictors of an eventual cancer diagnosis with negative or non-diagnostic FNA. These are simplistic but very important findings because improving the accurate identification of malignancy in patients with false-negative results on EUS-FNA is crucial. In the presence of a definite mass lesion or cystic lesion with either apparent invasion of the adjacent vessels or if lymph nodes are also present, patients should be considered at high-risk for malignancy and should be considered clinically different from patients without these findings. These findings would suggest a solid adenocarcinoma or in the case of a cystic neoplasm, a mucinous cystadenocarcinoma. These high-risk patients – despite a negative FNA – should be considered as having a false-negative FNA and followed closely with an early repeat attempt at tissue acquisition and repeat imaging, or strong consideration for direct referral to surgery if clinically applicable.
Our results also show that patients with a false-negative EUS-FNA had an eventual cancer diagnosis made in a relatively short time period after the EUS examination (). The mean time to a cancer diagnosis was only 66 days and the majority of patients who were diagnosed with cancer had the diagnosis made within 90 days after the EUS examination.
Only one patient was diagnosed with cancer at longer than five months after the initial negative EUS-FNA. This patient had a diagnosis of pancreatic adenocarcinoma made on autopsy almost a year to the day (360 days) after the EUS examination. These data have implications for how patients are monitored and followed after a negative EUS-FNA examination for a suspected pancreatic lesion. Patients who have cancer (the false negatives) will almost always be diagnosed with that malignancy within 90 days of the EUS examination and will tend to have EUS imaging characteristics (solid lesion, lymphadenopathy, vascular invasion) of a malignancy present despite a negative FNA. After three months and even more so after six months post-EUS examination, if a patient has not been diagnosed with cancer despite either clinical suspicion or CT imaging abnormality, and does not have suspicious EUS imaging, it is unlikely that a patient has an underlying malignancy that was missed at the time of EUS-FNA. Patients who do not have evidence of cancer six months after the EUS examination appear to need very little further imaging or surveillance of the pancreas. Thus, after a negative EUS-FNA in patients who do not have suspicious imaging findings on EUS, it is reasonable to perform one or two follow-up examinations such as a CT scan in the first six months after a negative EUS-FNA, but longer-term surveillance is rarely needed.
One weakness of the present paper is the inclusion of patients with all EUS findings such as solid lesions, cystic lesions and those without a definitive mass seen on EUS who still had an FNA. Cystic lesions are less likely to harbour an underlying malignancy than a solid-appearing lesion on EUS and cytopathology of pancreatic cystic lesions does not have the same sensitivity for malignancy as it does for solid lesions. However, we included patients with pancreatic cystic lesions and patients who did not have a clear mass because they still result in the same clinical dilemma of how to manage these lesions after a negative EUS-FNA diagnosis. With negative cytology on EUS-FNA of cystic lesions, decisions still need to be made on whether the patient is sent to surgery or how the patient’s cystic lesion should be followed. In the multivariate analysis, it did not matter if the lesion was cystic or solid because the presence of malignant-appearing nodes or vascular invasion still predicted the presence of a malignancy. Thus, despite negative FNA cytopathology in cystic lesions, the presence of significant findings (vascular invasion and lymphadenopathy) on EUS should prompt the physician to maintain a high suspicion of malignancy followed by close examination of the cyst fluid tumour markers, the clinical situation and the patient’s overall suitability for surgery. Furthermore, in our study, negative cytology and a cyst fluid CEA level of less than 200 ng/mL ruled out a cystic neoplasm in 90% of patients.
Close cooperation with the cytopathologists is needed as well as an understanding of the interpretation of the cytology findings on an EUS-guided FNA. For example, the clinician performing the examination needs to be aware of the difference that exists between the cytological diagnosis of atypical versus nondiagnostic. While neither result is ‘positive’ for malignancy, the patient with atypical cells on FNA obviously needs to be more closely followed after EUS-FNA with a higher suspicion of underlying malignancy than a nondiagnostic or negative cytology result.