Editorial: Endoscopic ultrasound-guided tissue acquisition in the era of precision medicine.

Comprehensive genomic profiling (CGP) of tumor tissues by next-generation sequencing (NGS) can identify significant mutated genes that may lead to genome-matched therapy and better prognosis. This is especially clinically relevant for pancreatic ductal adenocarcinoma (PDAC), as the majority of PDAC are diagnosed at an advanced stage and hence unresectable at the time of presentation. Thus, endoscopic ultrasound-guided tissue-acquisition (EUS-TA) not only plays a central role in diagnosis but is also essential for providing adequate tissue samples for CGP in the absence of surgical resected specimens. However, there are uncertainties regarding how to optimize EUS-TA to ensure sufficient tissue samples for CGP as different analytical platforms require different amount of tissue samples for successful CGP. Commercially available CGP (CACGP) tests include Onco-Guide™ NCC Oncopanel System (NOP; Sysmex Corporation, Hyogo, Japan) and FoundationOne® CDx (F1CDx; Foundation Medicine, Cambridge, MA). An optimal sample required for successful analysis by CACGP using formalin-fixed paraffin-embedded (FFPE) specimens is based on tissue surface area and tumor–nuclei ratio. Specimen adequacy for NOP is defined as tumor cell content ≥20% and tissue surface area ≥4 mm2, while that for F1CDx is defined as tumor cell content ≥20% and tissue surface area ≥25 mm2.1 Although a tandem, randomized controlled trial by Kandel et al. clearly demonstrated that specimen adequacy using F1CDx was significantly higher with FNB than with fine needle aspiration (FNA) needles,2 there are uncertainties about how EUS-FNB can be further optimized for CAGCP. Moreover, adequate tissue for diagnosis may not translate into sufficient tumor tissue for CAGCP. In this issue of Journal of Gastroenterology and Hepatology, Ishikawa et al. examined factors for optimization of EUS-FNB for CGP using F1CDx.3 This was a retrospective observational study in which EUS-FNB had been performed in 393 patients, predominantly PDAC (283 patients, 72%), of which 54 underwent F1CDx analysis. The first part of the study examined the optimal number of needle passes and cutoff value of macroscopic visible core (MVC) length considered as adequate sampling for genomic profiling. The second part of the study assessed factors related to the analytical success of F1CDx. There was a positive correlation between the acquisition rate and the number of passes using a 22-G needle (38.9%, 45.0%, 83.7%, and 100% for one, two, three, and four passes, respectively), while no correlation was found with a 19-G needle (84.2%, 83.3%, and 85.0% for one, two, and three passes, respectively). F1CDx analysis success rate was significantly higher with ideal samples than with suboptimal samples (94.1% vs 55.0%, P < 0.01). In addition, when analyzing an FFPE block made from tissue acquired for each needle pass against combined embedding of tissue from all needle passes into a single FFPE block, the success rate of analysis was significantly higher with combined embedding (100% vs 64.5%, P < 0.01). Important study limitations included the retrospective study design and the fact that not all specimens underwent concurrent F1CDx analysis. The former is a crucial point, as the methods of embedding differed after the cutoff date of May 2020, with separate and combined embedding used in the earlier and later time periods of the study, respectively. The subsequent analysis of results showed a 100% analysis rate with combined embedding, indicating that the method of tissue processing is also a factor that needs to be considered in CACGP, and not just the number of needle passes. The latter limitation should also be noted, as the gold standard for studies on tissue sampling and CGP is the success rate of genomic analysis. In relation to “combined embedding,” it should be highlighted that even when the tissue obtained from subsequent needle passes has been embedded in separate FFPE blocks, it is still possible to make specific arrangement with the pathology laboratory to combine the tissue sections cut from these blocks on the same unstained slide to be sent for CACGP for these small specimens. However, these limitations do not detract from the main study conclusions: (i) combined embedding was preferable as it was more likely to ensure successful CACGP; (ii) four needle passes were recommended as the optimal number when using a 22-G needle; and (3) MVC lengths ≥35 and ≥41 mm ensured an ideal sample when using 22-G and 19-G needles, respectively, which could be used as indicators for EUS-TA termination. Three other recent studies also investigated EUS-FNB acquisition rate for CACGP tests. Hisada et al. reported that in a cohort of 33 patients with unresectable PDAC who underwent EUS-FNB using a 19-G needle, the proportion that met NOP analysis suitability was 63.6%, making it a valid technique.4 In a cohort of 150 unresectable PDAC cases, Ikeda et al. found the use of FNB and 19-G needles were independent factors contributing to NOP analysis suitability and the analysis success rate was 100% for the 30 patients who underwent actual NOP analysis.5 Okuno et al. reported that in a cohort of 98 patients who underwent EUS-TA (82 pancreas target organ), the adequacy rate for CACGP testing was significantly higher with a 19-G FNB needle (72.5%), compared with 22-G FNB (53.5%) and 22-G FNA (33.3%) needles.6 The current study adds to the existing literature by further clarifying technical details needed to obtain sufficient tissue sample for improving the success rate of CACGP testing.3 Our understanding of the molecular pathology of cancer was deepened with the introduction of NGS technology. Detection of actionable mutations dramatically improves the prognosis of patients with advanced disease. EUS-FNB is well positioned as a reliable method for tissue acquisition for genomic analysis in the era of precision medicine.