Is there a role for endoscopic ultrasound-guided fine-needle biopsy in pancreatic cancer?

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has transformed the practice of diagnosing pancreatic adenocarcinoma by displacing surgical biopsy, and thus has resulted in lower cost, technical ease, and decreased morbidity [1]. However, there is now an increased demand for more precise “tumor-specific” diagnoses, as the treatment paradigm is shifting to a more personalized approach. This, in turn, has led to the need for better tissue fragments for cancer biomarker testing and grading. The two major limiting factors encountered in EUS-FNA are the quality and quantity of the tissue obtained. These limitations have prompted investigation into the use of larger-caliber needles, which have led to the analysis of fine-needle biopsy (FNB) as a workable alternative.

Intuitively, the assumption has been made that larger or more specialized needles would yield better tissue for subsequent molecular biological analysis and histologic grading. This issue of Endoscopy contains the report from a study by Larghi et al., which evaluated a standard 19-G or 19-G ProCore needle for performing preoperative EUS-FNB in 42 patients with pancreatic ductal adenocarcinoma (PDAC) [2]. Four experienced pathologists who were blinded to the results of surgical resection performed the histologic grading. The accuracy of preoperative grading of PDAC by EUS-FNB was 56 %, with significant heterogeneity and suboptimal agreement among the four pathologists (κ = 0.27; 95 % confidence interval 0.14 – 0.38). The results of this study suggest that EUS-FNB does not allow for reliable preoperative grading of PDAC. Moreover, these results align with the results of two other studies that were reported recently in Endoscopy. Lee et al. compared the ProCore needle with the standard FNA needle (n = 116) and found no significant difference in overall diagnostic accuracy (FNA 94.8 % vs. FNB 98.3 %; P = 0.67) or histological accuracy (FNA 77.6 % vs. FNB 82.8 %; P = 0.64) [3]. In a randomized, crossover study by Vanbiervliet et al. (n = 80), which used the standard 22-G FNA needle and 22-G ProCore needle, the quality of the tissue was statistically better with the standard needle as evaluated by two pathologists (expert 1, P = 0.009; expert 2, P = 0.002) [4].

The issue is not that FNB does not obtain histologic tissue, but rather it does not consistently obtain optimal (diagnostic and sufficient) tissue. This is supported by a recent study by Iwashita et al., which evaluated the macroscopic appearance of 111 biopsy specimens procured using the 19-G needle. Although a macroscopically visible core tissue was obtained in 91 %, histologic core tissue was seen in only 79 %, with a particularly high false-negative rate in pancreatic lesions [5]. Unlike surgical resection specimens, which embody the entire tumor, EUS-guided biopsies sample only a focal area of the suspected lesion. Histologic examination of such biopsies increases the probability of sampling and interpretation errors secondary to tumor heterogeneity. This is corroborated by two studies evaluating pancreatic neuroendocrine grading on EUS-FNA using the Ki-67 index. Both studies found high reproducibility and interobserver agreement when sufficient tissue was present, and significant discordance between the histologic and cytologic findings when limited EUS-guided material was evaluated [6] [7].

Advances in EUS tissue acquisition have been an iterative process, where continual re-evaluation of the best tools and techniques has indisputably led to its success. Therefore, in an effort to rectify our shortcomings, we must start by asking, “Is there truly a role for EUS-FNB in pancreatic malignancy?” and “What can we do to make EUS-FNB successful?”

Pancreatic ductal adenocarcinoma is extremely aggressive and carries a poor prognosis. There are limited therapeutic options, such as gemcitabine and paclitaxel, or leucovorin and fluorouracil, that have been shown to be efficacious in selected patients. Accordingly, there is an interest in tailoring chemotherapeutics to individual tumor biology. Histologic core tissue improves the yield for tissue microdissection and evaluation of molecular marker expression. MiRNAs that regulate various oncogenes (KRAS) and tumor suppressor genes (P16, P53, SMAD4, etc.) are being targeted as diagnostic analytes and predictors of response to neoadjuvant therapy. EUS-FNB may also serve to improve the diagnostic accuracy. A recent meta-analysis evaluated the frequency of atypical diagnoses in solid pancreatic lesions and found significant heterogeneity among the 23 studies with 206 atypical diagnoses. Results showed an inverse relationship between a diagnosis of “atypical” and “malignancy,” suggesting that some pathologists are either overly cautious or are under-diagnosing malignancy [8]. The evaluation of these specimens can be challenging, as tissue fragmentation can lead to artifactual changes and loss of histologic integrity. The presence of sufficient tissue would allow for diagnostic immunohistochemistry. One study reported molecular analysis of pancreatic EUS-FNB specimens for over-expression of P53 and found significant increase in the diagnostic accuracy from 79 % (EUS-FNA alone) to 92 % [9]. In addition, EUS-FNB may allow better prognostication with biomarkers and tumor grading. Certainly, reliable grading of pancreatic adenocarcinoma obtained by EUS-FNB preoperatively, would direct proper clinical management, accelerate the initiation of appropriate therapies, and obviate unnecessary procedures. The procedure can also aid in the diagnoses and characterization of unusual pancreatic malignancies, such as primary pancreatic sarcomas and lymphomas.

EUS-guided tissue acquisition is the preferred, more appealing, modality because of lower costs, simplicity, and efficiency. We have now exhausted the manual techniques to improve tissue acquisition. What is needed is an innovative biopsy needle that will allow better sampling from different trajectories and retrieval of longer, more intact, tissue fragments. If we demand this improvement in technology, we would no longer have to question whether EUS-FNB is needed – it would become the standard of care.

• References

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• 2 Larghi A, Correale L, Ricci R et al. Interobserver agreement and accuracy of preoperative endoscopic ultrasound-guided biopsy for histological grading of pancreatic cancer. Endoscopy 2015; 47: 308-314
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• 4 Vanbiervliet G, Napoléon B, Saint Paul MC et al. Core needle versus standard needle for endoscopic ultrasound-guided biopsy of solid pancreatic masses: a randomized crossover study. Endoscopy 2014; 46: 1063-1070
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